A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia

Background Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. Methods This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. Results The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases. Conclusion The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. Trial registration ClinicalTrials.gov identifier: NCT01716234

Size/Power/Level of Significance; Interim Analysis C avg is greater than or equal to 500 ng/mL. The sample size description was edited to reflect the updates to the study design. For clarification in these sections, the phrase "oral suspension" was added after "POS" in the name of the test product.

Pharmacokinetics
These sections were updated to note that the C avg will be used to compare the pediatric PK with the adult PK. The text that states steady-state trough samples will be compared against adult data was deleted. T he text that referred to exploring the use of a population PK approach to estimate AUC was deleted because this approach is not necessary for extensive PK sampling schemes. Adverse Events In the statistical methods and the statistical and analytical plans sections, the text for the AEs noted during the study was updated to reflect that the number of subjects reporting each AE will be presented by dose and age group (not treatment group).

Study Flow Chart
A new footnote b was added as a reminder that two baseline ECGs must be performed at least 5 minutes apart at the Baseline Visit for purposes of protocol eligibility. The footnotes in the study flow chart after this new additional footnote were re-lettered accordingly.

Study Procedures
The footnote in the study flow chart that states "During periods of neutropenia (ANC ≤500/mm 3 )" was deleted from the Baseline Visit (Day -1) for the absolute neutrophil count row for clarification. In the study procedures for absolute neutrophil count, the phrase "during periods of neutropenia (ANC ≤500/mm 3 )" was deleted. These changes were made for clarification because an absolute neutrophil count is to be performed for all subjects at the Baseline Visit. References to sections in the Investigator's Brochure were updated to the corresponding sections in the most recent version of the brochure.
In Age Groups 1 and 2, the first dose group will receive 12 mg/kg/day of oral POS divided into 2 doses (BID), up to a maximum of 800 mg per day, and the second dose group will receive 18 mg/kg/day of oral POS divided into 2 doses (BID), up to a maximum of 1200 mg per day. The third dose group will receive 18 mg/kg/day orally divided into 3 doses (TID), up to a maximum of 1200 mg/day. In Age Group 3, the first dose group will receive 12 mg/kg/day of oral POS divided into 3 doses, up to a maximum of 800 mg per day, and the second dose group will receive 18 mg/kg/day of oral POS divided into 3 doses, up to a maximum of 1200 mg per day. There will only be 2 dose groups for Age Group 3. The PK criteria for dose escalation are based on data from the adult population that found similar exposure following repeated administration of 400 mg BID and 600 mg BID. Doses above 800 mg per day were not found to be beneficial due to the plateau in POS exposure, which may also occur in pediatric subjects.
In subjects weighing >6.5 kg, PK samples will be drawn on Days 1 and 7, immediately prior to oral administration of POS and at approximately 3, 5, 8, and 12 hours from the time of oral administration of the morning dose for BID dosing. If TID dosing occurs, the 12-hour time point will not be drawn, and the 8-hour sample for subjects receiving TID dosing must be taken prior to the next dose. POS Cmin or trough samples (immediately prior to dosing) will be obtained on Days 3,5,8,14, and on Day 28 or within 24 hours after the last dose of study drug for early discontinuation. For Age Group 3 subjects (3 months to <2 years of age) weighing <6.5 kg, the samples will be taken as described above; however, there will be no PK samples taken on Day 1. In all subjects, both vital signs and laboratory blood tests will be performed throughout the treatment period and at 9 ±2 days of follow-up to assess the safety and tolerance of POS.  7. Subjects who are unable to receive study drug enterally. 8. Female subjects who are pregnant, intend to become pregnant during the course of the study, or are breastfeeding. 9. Subjects with a history of anaphylaxis attributed to the azole class of antifungal agents. 10. Subjects with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study, including receiving less than 7 days of POS. 11. Subjects who have already participated in this study or are participating in any Phase 1 clinical study or any study for a medication that has not yet received regulatory approval. Note: If the medication has received a regulatory approval for use in adults, then the medication would be considered to have received a regulatory approval for the purpose of this criterion. Any medication received by eligible subjects must also be aligned with the protocol guidance for prohibited medications (Table 3). 12. Subjects who are part of the study staff personnel or family members of the study staff personnel.
Test Product, Dose, Mode of Administration:

Age Group 1 (2 to <7 years) and Age Group 2 (7 to <18 years)
Dose Group 1: POS oral suspension 12 mg/kg/day orally divided into 2 doses, up to a maximum of 800 mg per day.
Dose Group 2: POS oral suspension 18 mg/kg/day orally divided into 2 doses, up to a maximum of 1200 mg per day.
Dose Group 3: POS oral suspension 18 mg/kg/day orally divided into 3 doses, up to a maximum of 1200 mg per day.

Age Groups 3 (3 months to <2 years)
Dose Group 1: POS oral suspension 12 mg/kg/day orally divided into 3 doses, up to a maximum of 800 mg per day.
Dose Group 2: POS oral suspension 18 mg/kg/day orally divided into 3 doses, up to a maximum of 1200 mg per day.
There is no Dose Group 3 for Age Group 3.
Reference Therapy, Dose, Mode of Administration: Not applicable.
Duration of Treatment: Subjects will receive study drug for at least 7 days and will continue to receive treatment until recovery from neutropenia (ANC>500/mm 3 ) or until initiation of standard of care for either empirical antifungal therapy, or for proven, probable, or suspected IFI. Subjects may receive a maximum of 28 days of study drug and the last study visit will be 9 days ±2 days after administration of the last dose of study drug. Survival assessment, if the subject is alive or dead, will be performed any day from Days 60 to 70. The overall study ends when the last remaining subject has completed or has been discontinued from the study.

Criteria for Evaluation
Pharmacokinetics: The POS plasma concentration-time data will be used to estimate the following PK parameters as the data allow: • Cmin: POS trough level immediately before a subject receives the dose on the day specified in the protocol. • CL/F: Total apparent body clearance at the steady state. The current blood samples schedule is an optimized schedule based on the adult steady-state PK data. If all blood samples can be collected at steady-state as scheduled, this optimized schedule will allow a calculation of the steady-state AUC by using non-compartmental trapezoidal method.
If more than one blood sample will be available for a patient, the concentration values will be averaged (Cavg). In case, all the planned blood samples can be collected from pediatric patients and an AUC can be calculated as described above, the Cavg will be calculated both by averaging all the concentrations in each subject and by dividing the AUC with dosing interval.
Safety: Safety will be assessed based on clinical laboratory test results, adverse events, physical examinations, vital signs, and electrocardiogram (ECG) results.
The occurrence of azole-associated toxicity will be evaluated.
Statistical Methods: Single dose and multiple dose plasma concentrations and derived PK parameters for POS will be listed and summarized by dose and age group using descriptive statistics.
The PK parameters, Cavg (and Cmax and AUC if data allow), will be log transformed for statistical analyses. Point estimates and 90% confidence intervals will be provided for each age group and dose level. If the confidence intervals indicate that ages do not produce a statistical difference on a PK parameter, then age groups will be pooled. To assess preliminary dose proportionality, log transformed, dose normalized Cavg (and Cmax and AUC if data allow) will be analyzed using analysis of variance (ANOVA) extracting the effect due to treatment. Ratio estimates and 90% confidence intervals will be calculated for the differences between doses and ages (if age groups are not pooled). The steady state analysis will be conducted using data from available PK trough values.
Comparison of the exposure from previous experience in adults will be conducted at steady state using graphics. A comparison between adult and pediatric patients with respect to the proportion of patients with steady-state Cavg greater than or equal to 500 ng/mL will also be conducted. If appropriate, comparisons between BID and TID dosing with respect to the steady-state Cavg and the proportion of patients achieving exposure above 500 ng/mL will be made.
Preliminary analysis will include examining the PK parameters for extreme values by reviewing the standardized ranges of deviations from the expected value derived from the model to see if any value exceeds 3. The impact of any outlier on the results of the analyses will be evaluated.
All AEs noted during the study will be listed. The number of subjects reporting each AE (by dose and age group) and severity will also be presented. Treatment emergent and treatment-related AEs will be tabulated by body system/organ class. The results of hematology and blood chemistry and physical examinations will be listed for each subject. Key toxicities, including hepatotoxicity and nephrotoxicity, will be tabulated by dose and age groups. If 4 or more out of 12 subjects within a dose/age group experience Grade 3 and Grade 4 toxicities in the same organ class which result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug, then DLT is reached. Assuming the chance of having grade 3/4 toxicity for a subject is 50%, then the probability of having 0, 1, 2, 3 or 4 subjects experiencing grade 3/4 toxicity within a dose/age group is 0%, 0%, 2%, 7% and 19%, respectively. Screening Note: Rising, multiple-dose, sequential-group study.

Day and Visit
The arrows represent that all escalation dose groups are to be progressed based on safety and tolerance. Each age group will escalate independently of the other. A PK and safety analysis of all available TID data across age groups will be performed after Age Group 2 Dose Group 3 completes enrollment of 12 PK-evaluable subjects. Oral POS 18 mg/kg/day (BID) or 18 mg/kg/day (TID) Oral POS 18 mg/kg/day (TID) Note: Rising, multipl e-dose, seq uential -group study.
a: Each of the high er POS dose regimen s in t he progression will not be administered until the safety and tolerabi li ty of the previ ously administered dose r egimens have been determi ned by the spo nsor. b: Group 3 will run after Groups 1 and 2. Group 3 is for Age Group 1 and Age Group 2 only. c: All patients may remain on stud y drug until recove ry from neutropenia (ANC>500/mm 3 ) or for a maximum duration of 28 days. d: Full PK Sampling time point s: predose, and at approxi mately 3, 5, 8, and 12 hours postdo se (12-hour samp le will not be obtaine d if dosing is TID, and the 8-hour samp le for subjects receivi ng TID dosing must b e taken prior to the next dose). For Age Group 3 subjects (3 months to <2 years of age) weighing <6.5 kg, the samples will be taken as described above; however, there will be no PK samples taken on Day 1. e: Trough levels will be obtained on Days 3,5,8,14,and 28 Table 5 A Summary of POS Plasma Concentrations in Pediatric Subjects ..99 Table 6 Summary of Adverse Events by Category, All Treated Subject .... 100 Table 7 Summary

Background
Posaconazole (POS; SCH 56592) is an oral broad-spectrum antifungal compound discovered by Schering-Plough Research Institute (SPRI). The mechanism of action is selective inhibition of the enzyme lanosterol 14 demethylase (CYP51A1) which is involved in ergosterol biosynthesis in yeasts and moulds. In adults, POS demonstrated superior response and survival in refractory aspergillosis compared to standard therapies. (1) Clinical success was also achieved in other difficult-to-treat refractory invasive fungal infections (IFIs), including fusariosis, (2) chromoblastomomycosis (3) and coccidioidomycosis. (4) POS demonstrated superior prophylaxis against IFIs and survival in neutropenic patients compared to fluconazole (FLU) or itraconazole (ITZ), (5) and superior prophylaxis and survival in hematopoietic stem cell transplantation (HSCT) recipients with graft versus host disease (GVHD) compared to FLU. (6) POS is also indicated as first-line therapy in the treatment of oropharyngeal candidiasis (OPC). (7) It has comprehensive in vitro activity equal to or superior to standard therapies as well. It is well tolerated with no dose adjustment required for renally impaired patients, and has limited potential for drug-drug interactions. It is anticipated that POS will provide the same therapeutic benefits in children as has already been demonstrated in adults.

Class or Type of Drug Being Studied/Description of Drug
POS is a broad-spectrum triazole antifungal compound that is being developed for the treatment and prophylaxis of IFIs.
POS oral suspension is provided as a 40 mg/mL aqueous suspension, the components of which are described in the Investigator's Brochure. (8) Please refer to Section 8.1 of the Investigator's Brochure for additional information. (8)

Preclinical Profile
POS administered orally is supported by an extensive preclinical and clinical program. POS causes several toxicologic effects that occur with other antifungal substances in the azole class, ie, hyperplasia of the adrenal glands (rats, mice, and dogs), phospholipidosis of lung and lymphoid tissues (all species), disseminated intravascular coagulation (dogs only), bone thinning/fractures (rats only), hepatocellular adenomas (mice only), findings secondary to the interruption of steroidogenesis and fetal toxicity (rats and rabbits with no functional consequence), increased urinary calcium excretion in dogs and rats, histiocytic hyperplasia of lymph nodes of mice, and adrenal cortical and medullary tumors in rats, resulting from interrupted steroidogenesis and altered calcium homeostatis, respectively.
POS oral had no effect on fertility of male or female rats. In studies of embryo and fetal development in the rat at POS oral doses of 3 mg/kg, 9 mg/kg, or 27 mg/kg, the highest dose caused skeletal malformations, while the no-effect dose was 9 mg/kg POS oral. In the rabbit, the no-effect dose of POS oral was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg caused an increase in resorptions. A POS oral dose of 80 mg/kg also caused a reduction in female body weight gain and in litter size. No malformations were noted in rabbits. In a peri-and post-natal study, adverse reproductive effects including dystocia, prolonged parturition, reduced F1 mean live litter size and reduced F1 postnatal viability occurred at POS oral doses of 18 mg/kg and above, but not at 6 mg/kg. However, there were no effects on functional battery endpoints in the F1 generation. Embryo resorptions, postimplantation losses, delayed parturition, as well as fetal skeletal malformations and variations are class effects of azole antifungal drugs.
Although maternal or pup exposure to POS was not determined in the peri-and post-natal developmental toxicity study, a lactational transfer study confirmed exposure to POS in pups, and exposure data are available at similar doses from the rat carcinogenicity study that was conducted at 5 (male [M] + female [F]), 10 (M + F), 20 (F) and 30 mg/kg (M). The average steady-state plasma concentration (C avg ) achieved in the 10 mg/kg dose group represents exposure multiples of 3.21 and 7.67, for males and females, respectively, relative to the C avg achieved in pediatric subjects administered 800 mg per day POS in divided doses for the treatment of refractory IFIs (P00041; N=12; 8 to 17 years of age). When compared with the C avg achieved in 10 adolescents (13 to 17 years of age) who received 600 mg/day in divided doses for prophylaxis (P01899), the exposure multiples are 3.59 and 8.57 for males and females, respectively. Therefore, the exposure achieved in the animal peri-and post-natal developmental toxicity study was ~3-to ~9-times greater than the exposure achieved in pediatric subjects.

Pharmacokinetics
The pharmacokinetics (PK) of POS oral is linear following single-and multiple-dose administration up to 800 mg. No further increases in exposure are observed above 800 mg in patients and healthy volunteers. Dividing the total POS daily dose (800 mg) as 400 mg twice daily (BID) results in a 192% higher mean average concentration relative to once-a-day administration in patients (P01893 administered with a nonfat meal or nutritional supplement (14 g fat) and 4 times greater when administered with a high-fat meal (~50 g fat) relative to the fasted state. POS should be administered with food or a nutritional supplement. POS has a large apparent volume of distribution (1774 L) suggesting extensive penetration into the peripheral tissues. Of the circulating metabolites, glucuronide conjugates of POS are major metabolites, with only minor amounts of Phase 1 (CYP450) metabolites. POS is slowly eliminated with a mean half-life (t½) of 35 hours. POS is predominantly excreted in the feces (77% of the radiolabeled dose) with the major component eliminated as parent drug (66% of the radiolabeled dose). Steady state is attained following 7 to 10 days of multiple-dose administration.
Please refer to Section 8.1.1 of the Investigator's Brochure for additional details. (8)

Pediatric Pharmacokinetics
The POS exposure data obtained thus far from pediatric subjects outside of the current study is summarized in Table 2: Analysis of POS concentration by age, weight and body surface area (BSA) did not show any correlation (Figure 1, Figure 2, and Figure 3). (9) Limited PK data are available from pediatric subjects less than 7 years of age.   In addition, rare cases of torsades de pointes, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported in patients with significant underlying medical conditions who were treated with POS.
In summary, completed and ongoing laboratory and clinical studies in a wide variety of azole susceptible and refractory fungal infections have demonstrated that POS has a broad spectrum of activity and is safe and well tolerated.

Pediatric Experience
Up to 31 MAR 2012, a total of 226 subjects <18 years of age received treatment with POS. The two youngest subjects exposed to POS were 22 and 23 months old, and were enrolled under special exemption in a compassionate-use protocol (P02095). Dose adjustments were recommended for pediatric subjects weighing less than 34 kg. The compassionate-use program (P02095) enrolled 129 pediatric subjects of different races.
A review of the safety and PK data from Age Groups 1 and 2 from the first two dose groups from the current study (P03579) was performed by the external Data Monitoring Committee and the Sponsor. No safety concerns were identified. The POS PK exposure target for the study, ~90% of subjects with POS steady-state C avg in the range of 500 ng/mL to 2500 ng/mL, has not been achieved at either dose level (Appendix 4).
For further details regarding the safety of POS in pediatrics, please refer to Section 8.2.2.8 of the Investigator's Brochure (8) and Appendix 4 for the P03579 safety and preliminary PK results.
The comparability of the PK of POS in pediatrics versus adults, and the similarity in the proportion of pediatric subjects reporting serious adverse events (SAEs) or other clinically significant adverse events versus the overall adult patient population by study, indicate that the safety profile in pediatrics appears to be comparable to that in adults.

Project Rationale
IFIs are a leading cause of infectious disease mortality in immunocompromised patients. The pediatric patient population at risk for developing IFIs is similar to adults, and includes, but is not limited to allogeneic stem cell transplant recipients, patients with acute leukemias, myelodysplasia, severe aplastic anemia, and advanced stage non-Hodgkin's lymphoma. Incidence of IFIs in pediatric patients with cancer ranges from 5% to 20%, (10)(11)(12)(13)(14)(15) but this incidence is higher in certain subgroups such as recipients of stem cell transplants (up to 16%), (14) patients with acute leukemia (10% to 20%), (5,6) or acute myelogenous leukemia (9%), for example. (11) POS is a potent triazole antifungal agent with a wide spectrum of activity against both pathogenic yeasts and moulds, and may be useful in pediatric patients who are at risk for developing IFIs. Clinical studies in subjects (13 years of age) using POS oral therapy (P00041, P01893, C/I96-421, and P01899) support the efficacy of POS in the treatment of severely immunocompromised patients, either to prevent IFIs (prophylaxis) or as salvage therapy (to treat IFIs that have failed standard antifungal therapy).
In addition, PK, safety and efficacy data for POS in children are sparse. Limited PK data are available for pediatric subjects <7 years of age, and no PK or safety data are available for pediatric subjects <2 years of age. Neither the prophylaxis dose nor the treatment dose for Aspergillus and Candidiasis have been established for patients <13 years of age, and the treatment dose for OPC has not been established for patients <18 years of age.

Study Rationale
Exposures to POS (dosing and levels) associated with clinical efficacy correlated well with levels at or above minimum inhibitory concentrations (MICs) for the pathogens treated or most common pathogens prevented. In a pivotal prophylaxis trial that showed survival benefit, clinical failure appeared to be correlated with the extent of POS exposure. In these studies, study efficacy was correlated with POS plasma concentrations of 500 ng/mL or greater. Thus, targeting same or better POS exposure levels in children of a similar population may confer similar or better protection and efficacy achieved in previous adult studies. In addition, a safety and PK trial of POS is an important step in understanding the safety and pharmacology of POS in children and ultimately, reducing morbidity and mortality related to IFIs in this population.

Study and Dose Rationale
This study is designed as a nonrandomized, multicenter, open-label, sequential dose-escalation study to evaluate the safety, tolerance, and PK of POS. It will include pediatric patients of different age groups to determine if there are differences in exposure to POS affected by differences in drug metabolism related to developmental changes in pediatric patients that may affect the primary pathway for POS metabolism, glucuronidation, and the enzyme (UGT1A4) which is not fully developed until ~2 years of age. Since factors of drug absorption, metabolism, distribution, and elimination are all affected by the age and physiologic maturity of the child, the inclusion of different age groups in this population may help to determine the dose to be used for treatment and prophylaxis of fungal infections in pediatrics.
The proposed starting dose for this trial, 12 mg/kg/day, was chosen based on previous experience with POS in adult and pediatric subjects ranging in age from 7 years to 17 years. In the treatment study (P00041) all subjects received 800 mg POS per day, or 11 mg/kg/day for a 70 kg adult. The majority of pediatric patients (8 years to 17 years of age) received the full adult dosing regimen, within the range of 15 mg/kg/day to 24 mg/kg/day. Despite slight differences in dose, the C avg achieved in adults (844 ng/mL) was similar to the C avg achieved in pediatrics (776 ng/mL). In the prophylaxis studies, subjects received 600 mg day, or 8.5 mg/kg/day for a 70 kg adult, which also provided similar exposure in adults (C avg = 578 ng/mL) as in pediatric subjects (13 years to 17 years of age; C avg = 694 ng/mL). Given that the systemic exposure to POS was similar between pediatric subjects and adults, and was not influenced by age, weight or body surface area, it is anticipated that the starting dose of 12 mg/kg/day may result in exposures that are similar to those observed in the pediatric and adult populations at this approximate dose, and for which efficacy has already been established in adults.
In addition, in healthy volunteers and patients, no increase in the incidence or severity of adverse events was observed at higher exposures compared with lower exposures and the data obtained thus far indicate that the safety profile appears to be similar between adults and children. The vast majority of SAEs observed in children were unlikely to be related to POS, reflecting the serious and advanced nature of the IFI and underlying medical illnesses. Nevertheless, the study design includes an assessment for safety for the first 6 subjects treated at each dose level for each age group employing rapid data collection and centralized analyses. When safety has been assessed for the lowest dose group by the Sponsor and the external Data Monitoring Committee, and a determination has been made that the safety data are adequate to support enrollment into the next higher dosing level, then subjects will be screened and treated. An assessment of differences in exposure between the first two dose groups will be conducted to determine whether TID dosing will be subsequently explored. Subjects in the youngest age group (3 months to <2 years of age) will not be administered POS until the safety and PK data from the two older age groups and first two dose groups have been evaluated by the Sponsor and the external Data Monitoring Committee. Therefore, key decision points for advancing the dosing to the next dosing group will be based on the combination of frequency and severity of untoward effects.

Primary Objective
The primary objective of this study is to evaluate the PK of POS administered orally at three dosage levels to immunocompromised children with neutropenia or expected neutropenia aged 3 months to <18 years.

Secondary Objective(s)
The secondary objective of this study is to evaluate the safety and tolerability of POS administered orally at three dosage levels to immunocompromised children with neutropenia or expected neutropenia aged 3 months to <18 years, and to compare the exposures to POS in pediatric subjects to those from an adult population with similar underlying conditions.

Design of the Study/Methodology
This will be a non-randomized, multicenter, open-label, sequential dose-escalation PK study. Subjects enrolled will be immunocompromised children with neutropenia or expected neutropenia between the ages of 3 months to <18 years. Those febrile subjects with proven IFI prior to entry will not be enrolled. For any subject who meets institutional criteria to start standard empirical or pre-emptive antifungal therapy or who has a proven breakthrough fungal infection, POS will be discontinued and pre-emptive or empirical therapy with standard of care will be initiated. A breakthrough fungal infection is defined as microbiological or histological evidence of a deep mycosis developing while a subject is receiving study drug. Subjects must receive one or more doses of POS to be evaluable for toxicity.
If a subject in a given dosage level and age group receives fewer than 14 consecutive doses for BID dosing or 21 consecutive doses for TID dosing, or fails to complete Day 8 trough PK sample collection for reasons other than drug intolerance, a replacement subject may be entered at that dosage level and age group. PK samples will be drawn on Days 1 and 7 in subjects weighing >6.5 kg; Age Group 3 subjects (3 months to <2 years of age) weighing <6.5 kg will have PK samples drawn on Day 7, but no PK samples will be taken on Day 1. Additionally, in all subjects, POS minimum observed plasma concentration (C min ) or trough samples (immediately prior to dosing) will be collected on Days 3, 5, 8, 14, and 28 or within 24 hours after the last dose of study drug administration for early discontinuation. In addition, vital signs and laboratory blood tests will be performed throughout the treatment period and at 9 days ±2 days of follow-up to assess the safety and tolerance of POS.
Subjects will not be re-enrolled onto this study. If a subject is assigned a subject number, but does not receive study drug, the subject number will not be used again.
All subjects may remain on study drug for at least 7 days and until recovery from neutropenia (absolute neutrophil count [ANC]>500/mm 3 ) or for a maximum duration of 28 days.
Oral POS will be administered at one of three dosage levels in the 2 older age groups (Age Group 1 [2 years to <7 years] and Age Group 2 [7 years to <18 years]) and at one of two dosage levels in the youngest age group (Age Group 3 [3 months to <2 years of age]). Study drug will not be administered to the higher dosage group in a given age group until after safety data obtained in at least 6 completed subjects in the lower dosage group in a corresponding age group are reviewed independently by the external Data Monitoring Committee and the Sponsor. Additionally, the subjects in the youngest age group (3 months to <2 years of age) will not be enrolled until all safety and PK data obtained from the two older age groups in the first two dosage levels are reviewed independently by the Sponsor and external Data Monitoring Committee.
For Age Group 1 (2 years to <7 years) and Age Group 2 (7 years to <18 years), the first dose group (Dose Group 1) will receive a total of 12 mg/kg/day of oral POS, divided into 2 daily doses (BID), up to a maximum of 800 mg per day. Within a given age group, escalation to the 18 mg/kg/day can initiate if no more than 2 out of the 6 subjects experience Grade 3 and Grade 4 toxicities in the same organ class which pursuant to protocol item Section 7.7.2.2 result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug. The second dose group (Dose Group 2) will receive 18 mg/kg/day of oral POS, divided BID, up to a maximum of 1200 mg per day. For Age Groups 1 and 2, a third dose group (Dose Group 3) will receive 18 mg/kg/day orally divided into 3 doses (TID), up to a maximum of 1200 mg/day. If 4 of 12 subjects experience Grade 3 and Grade 4 toxicities in the same organ class which pursuant to protocol item Section 7.7.2.2 result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug at a given dose level, then the maximum tolerated dose (MTD) will have been reached. For Age Group 3 (3 months to <2 years of age), there will only be two dose groups, Dose Groups 1 and 2; subjects will be administered as 12 mg/kg/day (divided TID) or 18 mg/kg/day (divided TID), in Dose Group 1 and 2, respectively.
The PK criteria are based on data from the adult prophylaxis and treatment studies in which doses above 800 mg per day were not found to be beneficial due to the plateau in POS exposure, which may also occur in pediatric subjects.
The 24 subjects in the youngest age group (Age Group 3 [3 months to <2 years of age]; n=12/dosage group) will receive POS in the same manner using the same criteria for dose escalation and dose-limiting toxicity, and starting with the same total daily dose as the two older age groups. Based on the review of the safety and PK data in the older age groups, the youngest age group will start with a total daily dose divided TID, instead of BID.
All POS doses will be based on the actual body weight at baseline which should be continued through the treatment period.
Escalation to the next higher dosage level will be permitted after mutual agreement by the Sponsor and the external Data Monitoring Committee.
All subjects in a given dosage group do not have to be enrolled and assessed before escalation to the next dosage level. Age Groups 1 and 2 will dose-escalate independently of each other.

Screening
Within 10 days prior to treatment, the investigator or qualified designee shall discuss with the parent(s) or legal guardian of each subject, and with each subject as appropriate, the nature of the study, its requirements, and its restrictions. Written informed consent will be obtained from the parent or legal guardian of each subject prior to any study related procedures being performed, and a signed copy will be given. Assent will be obtained from minors according to institutional practices. The inclusion/exclusion criteria will be reviewed, a demographic profile, complete medical history, medication review, physical examination and other assessments delineated in Section 2.2, Study Flow Chart, (eg, height determination, vital signs [blood pressure, heart rate and temperature]) will be performed. Blood samples will be collected for evaluation of eligibility criteria and for safety assessments (eg, pregnancy test, clinical safety laboratories, etc). A screening number will be assigned to the subject on completion of the study-specific informed consent. Assessment of SAEs after signature of the Informed Consent will also be recorded.

Baseline
The investigator or designee will review the inclusion/exclusion criteria and record medications taken within the last 14 days (chemotherapeutic agents taken within 30 days of the first dose of study drug). A physical examination, vital signs, 12-lead electrocardiogram [ECG], and chest radiograph (as clinically indicated to evaluate for fungal infection) will be performed, as well as an assessment of AEs. ANC will be determined. Weight will be measured.

Treatment Day(s)
Subjects will initiate treatment following standard intensive induction or consolidation chemotherapy cycle. Subjects will receive their treatment at approximately the same time every day on Days 1 through 28. Each dose will be administered approximately 12 hours apart for BID regimens and approximately 8 hours apart for TID regimens. Laboratory safety tests (eg, hematology, blood chemistries, and ECG), vital signs, ANC, adverse events, concomitant medications, and dietary food intake assessment will be collected according to the schedule in Section 2.2, Study Flow Chart. Meals, including formula or breast milk, will be provided in accordance with the meals section of the protocol Section 7.4.2.2.1, Diet. For subjects weighing >6.5 kg, serial PK samples will be obtained from prior to dosing until 12 hours after the morning dose on Days 1 and 7 for BID dosing; age Group 3 subjects (3 months to <2 years of age) weighing <6.5 kg will have PK samples drawn on Day 7, but no PK samples will be taken on Day 1. If TID dosing is required, the 12-hour sample will not be obtained, and the 8-hour sample following TID dosing must be taken prior to the next dose.
In all subjects, POS C min or trough samples (immediately prior to dosing) will be drawn on Days 3, 5, 8, 14 and 28, or within 24 hours after the last dose of study drug administration for early discontinuation.
On the last day, adverse events, concomitant medications, and dietary food intake assessment will be recorded, a blood sample will be collected for laboratory safety tests, and vital signs and body weight will be recorded.

Last Study Visit
Follow-up will be conducted 9 days ±2 days after the last day of study drug administration. Adverse events and concomitant medications will be recorded, a sample will be collected for laboratory safety tests, and vital signs will be recorded. ANC will be determined as clinically indicated.

Survival Assessment
Survival assessment, if the subject is alive or dead, will be performed any day from Days 60 to 70. If the subject dies, the date of death will be recorded.

Plasma/Serum Samples
For all subjects >6.5 kg, approximately 25 mL of blood will be collected from each subject: • 15 samples/subject, 1 mL/sample for PK, • 9 samples/subject, 1 mL/sample for safety, and • 1 sample/female of childbearing potential, 1 mL/sample for pregnancy test.
For subjects in Age Group 3 weighing <6.5 kg, approximately 18 mL of blood will be collected from each subject, as no PK samples will be collected on Day 1.

Participation in and Completion of the Study
The subject is considered to be enrolled in the study when the subject signs the study specific informed consent. All subjects will have their information entered into the screening log maintained by the study site, and will have information (demographics and reason for screening failure) entered into the eCRF.
The subject is considered to have completed the study upon the completion of the last protocol-specified contact (eg, visits or telephone contacts).
Study treatment may be discontinued prior to completion for the reasons described in Section 7.3.3, Subject Discontinuation Criteria. For those subjects who do not complete the study, subject participation will be considered terminated upon the completion of the last visit or contact (eg, phone contact with the investigator or qualified designee).
The overall study ends when the last remaining subject has completed or has been discontinued from the study.
Once a subject has ended participation in the study, study drug will no longer be available to the subject and he/she will revert to standard care according to his/her personal physician.

Study Population
The 3 age groups selected, 3 months to <2 years, 2 years to <7 years, and 7 years to <18 years represent distinct groups based on epidemiology characteristics as well as potential differences in age-related maturation that may affect the PK of drugs. Pediatric subjects with neutropenia or those expected to be neutropenic (ANC ≤500/mm 3 ), following standard intensive induction or consolidation chemotherapy will be selected for the study. Approximately 96 PK-evaluable subjects will be enrolled among the study sites.

Subject Inclusion Criteria
The subject must meet ALL the criteria listed below for entry: 1. Children of either sex and of any race, 3 months to <18 years of age. 2. Subjects' parent or legally authorized representative must be willing to give written informed consent. Assent will be obtained from minors according to institutional practices. 4. Male and female subjects of child-bearing potential must agree to use a medically accepted method of contraception throughout the study and for at least 30 days after stopping the medication, unless they are surgically or medically sterile or agree to abstain from sexual intercourse. Acceptable methods of contraception include 2 of the following: a. Condoms (male or female) with spermicide, b. Diaphragm or cervical cap (if acceptable according to local standard of care) with spermicide (female), c. Hormonal contraceptives or intrauterine device with spermicide (female).

Subject Exclusion Criteria
The subject will be excluded from entry if ANY of the criteria listed below are met:  Table 3). 5. Subjects whose laboratory tests are outside normal limits, as follows: a. AST or ALT >5 times the upper limit of normal (ULN) b. Serum total bilirubin >2.5 x ULN c. Calculated creatinine clearance <30 mL/min. Creatinine clearance will be calculated using the following equation: Creatinine clearance = k*height (cm)/serum creatinine (mg/dL) Where k = 0.45 for a full term baby less than 1 year old; 0.55 for children up to 12 years old; 0.55 for females between the ages of 13 and 21 years; 0.7 for males between the ages of 13 and 21 years. 6. Subjects with QTc prolongation: a. Symptomatic QTc prolongation >450 msec (males) or >470 msec (females); b. Any QTc prolongation of >500 msec. 7. Subjects who are unable to receive study drug enterally. 8. Female subjects who are pregnant, intend to become pregnant during the course of the study, or are breast-feeding. 9. Subjects with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study, including receiving less than 7 days of POS.  10. Subjects with a history of anaphylaxis attributed to the azole class of antifungal agents. 11. Subjects who have already participated in this study or are participating in any Phase 1 clinical study or any study for a medication that has not yet received regulatory approval. Note: If the medication has received a regulatory approval for use in adults, then the medication would be considered to have received a regulatory approval for the purpose of this criterion. Any medication received by eligible subjects must also be aligned with the protocol guidance for prohibited medications (Table 3). 12. Subjects who are part of the study staff personnel or family members of the study staff personnel.

Subject Discontinuation Criteria
Study treatment may be discontinued during the study for any of the following reasons: • • Other systemic antifungal agents are indicated for proven IFI; • Subjects who, following Baseline require any of the prohibited medications listed in A subject who develops a superficial fungal infection (eg, cutaneous fungal infection, thrush or candidal vaginitis) may be treated with topical antifungal agents (nystatin and/or azole formulations) and continued on study drug if in the judgment of the investigator there is no evidence of systemic involvement or more extensive mucosal involvement that would require more specific systemic antifungal therapy. Superficial candidiasis (including signs and symptoms and supporting laboratory findings) must be noted on the eCRF.
It is the right and the duty of the investigator or subinvestigator to interrupt treatment of any subject if he/she feels that study discontinuation is necessary to protect the subject, or that there are unmanageable factors, that may interfere significantly with the study procedures and/or the interpretation of results.
If a subject discontinues prior to completion of the study, the reason for the discontinuation will be obtained. The date of the last dose of study medication and the date of the last assessment and/or contact will be obtained. This information will be documented in the appropriate section of the eCRF. A follow-up contact (telephone or visit) will be arranged as appropriate.
At the time of discontinuation, every effort should be made to ensure all procedures and evaluations scheduled for the final study visit are performed (Section 2.2, Study Flow Chart and Section 7.6, Study Procedures). For all discontinued subjects, AEs should be recorded and medication compliance should be assessed. Any returned drug should be inventoried.

Replacement of Subjects
If a subject in a given dosage level and age group receives fewer than 14 consecutive doses for BID dosing or 21 doses for TID dosing, or fails to complete Day 8 trough PK sample collection for reasons other than drug intolerance, a replacement subject may be entered at that dosage level and age group.
After consultation between the Sponsor and the principal investigator, enrollment may be extended to replace subject(s) discontinued during the study.

Study Treatments
Upon acceptance into the study, once all the inclusion criteria are met and none of the exclusion criteria are met on Day 1, subjects (2 years to <18 years of age) will be enrolled. Twelve subjects per dose group will be enrolled in the following age groups: 2 years to <7 years (Age Group 1) and 7 years to <18 years (Age Group 2).
The first dose group of 24 subjects in Age Groups 1 and 2 (2 years to <18 years) will receive POS at a total dose of 12 mg/kg/day, divided twice daily (BID), up to a maximum of 800 mg per day. If no more than 2 of the first 6 subjects in a given age group experience Grade 3 and Grade 4 toxicities in the same organ class which pursuant to protocol item Section 7.7.2.2 result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug, initiation of the second dose group may begin. The second dose group of 24 subjects in Age Groups 1 and 2 will receive POS at a dose of 18 mg/kg/day, divided twice daily (BID), up to a maximum of 1200 mg per day. The third dose group for Age Groups 1 and 2 will receive 18 mg/kg/day orally divided into 3 doses (TID), up to a maximum of 1200 mg/day.
The 24 subjects in the youngest age group (Age Group 3 [3 months to <2 years]; n=12/dosage group) will receive POS in the same manner using the same criteria as the two older age groups, starting at the same time as the third dose group in the 2 older age groups (Age Groups 1 and 2). Based on the review of the safety and PK data in the older age groups, the youngest age group (Age Group 3) will start with a total daily dose divided TID, instead of BID. The starting dose for the youngest age group will be 12 mg/kg/day divided into 3 doses, up to a maximum of 800 mg per day. If no more than 2 of the first 6 subjects in a given age group experience Grade 3 and Grade 4 toxicities in the same organ class which pursuant to protocol item Section 7.7.2.2 result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug, initiation of the second dose group may begin. The second dose group of 12 subjects in Age Group 3 will receive POS at a dose of 18 mg/kg/day divided into 3 doses, up to a maximum of 1200 mg per day. There will only be 2 dose groups for Age Group 3. If the target POS exposure level is not achieved with POS at a dose of 18 mg/kg/day divided TID in this youngest age group, there will not be further dose escalation for this age group.
In all treatment groups, subjects will receive study drug for at least 7 days, and until recovery from neutropenia (ANC>500/mm 3 ) or a maximum duration of 28 days, whichever occurs first. All POS doses will be based on actual body weight at baseline which should be continued throughout the treatment period. If four of twelve subjects experience Grade 3 and Grade 4 toxicities in the same organ class which pursuant to protocol item Section 7.7.2.2 result in definitive discontinuation of study drug treatment and are believed to be potentially cause-related to study drug, then dose limiting toxicity (DLT) will be reached.

Treatments Administered
POS oral suspension dosing will be administered using the Sponsor-supplied 1-mL, 3-mL, or 10-mL oral dosing syringe. For infants, doses may be administered by gavage using an appropriately sized oral dosing syringe provided.
Six different sizes of oral dosing syringes (0.5 mL, 1.0 mL, 3.0 mL, 5.0 mL, 10.0 mL, and 20.0 mL) were evaluated in a dose recovery study by the Sponsor, and there was no significant difference found in the recovery of POS oral suspension from these sizes of oral syringes relative to control samples. Various sizes of syringes allow for accurate dosing of POS using the current pediatric dosing procedure. (17) For a subject that has a feeding tube made of polyvinyl chloride (PVC), silicone, or polyurethane inserted for nutritional support and who does not have any contraindication for enteral feeding, POS oral suspension can be administered via the enteral feeding tube (e.g. gastric or nasogastric tube). Feeding tubes made of PVC, silicone, or polyurethane have been evaluated in a study by the Sponsor and were found to be compatible with POS oral suspension. (17) There is no information on compatibility or dose recovery with feeding tubes made of other materials.
POS oral doses will be administered within approximately 10 minutes after completion of a meal or oral liquid nutritional supplement, or in the case of infants, after a bottle or breast-feeding. For subjects with enteral feeding tubes, POS oral suspension administration must be followed by a flush of the tube, preferably with the same infusate given for feeding (nutritional supplement). The flush volume should be at least the same volume as the volume of the enteral tube (e.g., 10 mL) taking in consideration the diameter of the tube, manufacturer's specifications, and the local standard of care.
Each dose should be administered at approximately the same time each day, approximately 12 hours apart for subjects receiving BID dosing and approximately every 8 hours for subjects receiving TID dosing. On days when trough sampling is done, meals and dose will be held until the predose blood sample has been obtained. A dietary food intake assessment will be performed on Days 1 through 28 or last day of study drug treatment. See Appendix 2, Posaconazole Oral Administration, for the detailed POS oral treatment preparation and administration procedures.
Dosing Groups for Age Group 1 (2 years to <7 years) and Age Group 2 (7 years to <18 years) Group 1: POS oral suspension 12 mg/kg/day orally divided into 2 doses (BID), up to a maximum of 800 mg per day.

Group 2:
POS oral suspension 18 mg/kg/day orally divided into 2 doses (BID), up to a maximum of 1200 mg per day. There is no planned third dosing group for Age Group 3.

Timing of Dose for Each Subject
All POS oral doses will be taken with food or oral liquid nutritional supplement containing fat calories (eg, Ensure®, Sustacal, etc). For infants who are being fed either formula or breastmilk exclusively, POS oral doses should be taken after a feeding. This is consistent with the conditions in which studies of the absorption, metabolism, and elimination of oral 14 C POS were performed. POS oral doses will be administered within approximately 10 minutes after completion of a meal or oral liquid nutritional supplement. If for any reason the timing of the medication needs to be adjusted after the first dose, the dose time may be adjusted by  6 hours for BID dosing and  3 hours for TID dosing.
Subjects should be observed for 30 to 60 minutes after the first dose for tolerance of study drug. Subjects who vomit within 30 minutes of POS oral administration should be given a single replacement dose. Repeated episodes of vomiting should be indicated on the Adverse Event eCRF and the Dosing eCRF.

Method of Treatment Assignment, Randomization, and/or Stratification
No randomization will be performed. Subjects will be stratified into the following age groups: Age Group 1: 2 years to <7 years of age

Management of Blinding of Study Treatments
This is an open-label study with no blinding.

Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, handling, storage, distribution, and usage of these materials in accordance with the protocol and any applicable laws and regulations.
The following Investigational product will be used in the study and will be supplied in sufficient quantities for subjects and any replacement subjects.
• POS Oral Suspension 40 mg/mL, will be supplied as 105-mL fill in 120-mL bottle.

Identity of Investigational Product(s)
Please see the Investigator's Brochure for description of investigational drug product. (8) Subjects will receive the following antifungal agent: • POS suspension is supplied in 40 mg/mL strength.

Source
The Sponsor will provide the investigational product for this study.

Labeling, Storage and Dispensing
Each POS oral suspension bottle will be labeled in a standard open-label fashion in accordance with Good Manufacturing Practice (GMP) for clinical trials and country specific guidelines. The label on each bottle will include the drug name, strength, study number, a unique alpha-numeric number (Packaging Request number or Lot number), storage conditions and an investigational use statement. Additional country-specific requirements may be added to the label. The label on each POS oral suspension bottle will include the following instructions: Shake well before use. Take with meals or immediately after eating. Spaces will be provided on each oral bottle label for the recording of the study site, patient number, date dispensed, amount to be administered and bottle number.
Study drug supplies must be stored in a secure, limited-access location under the storage conditions specified on the drug supply label.
Receipt and dispensing of study medication must be recorded by an authorized person at the investigator's site.
The investigator agrees neither to dispense the study drug from, nor store it at any site(s) other than those listed on the Form Food and Drug Administration (FDA) 1572 or Investigator's Agreement. The investigator agrees that study drug(s) will be dispensed by the investigator or subinvestigator(s) named on the Form FDA 1572 or Investigator's Agreement, or their qualified designees. The investigator, subinvestigators, or qualified designees also agree that the study drug(s) will be dispensed only to study subjects or parents or legal guardians of subjects from whom written informed consent has been obtained, and have met all entry criteria. Clinical supplies may not be used for any purpose other than that stated in the protocol.
An adequate quantity of study drug will be provided to replace units damaged in shipment/handling, to replace subjects meeting the entry criteria or to enroll additional subjects at intermediate or higher dose levels.

Packaging
Study drug will be packaged in bulk, 6 bottles per box.

Drug Accountability
The subjects or their parent(s) or legal guardians will be instructed to return all unused and partially used test articles at all protocol-specified visits for drug inventory and assessment of subject compliance.
An accurate and current accounting of the dispensing of study drug(s) for each subject will be maintained on an ongoing basis by a member of the study site staff in a test article accountability ledger (TAAL) or equivalent document and the eCRF and will be verified by the Sponsor's study monitor.
All drug supplies, including all containers of study drug, whether empty or containing unused or partially used study drug, must be returned to the Sponsor or its designee, unless investigators are instructed otherwise by the Sponsor or its designee. The Sponsor's study monitor will provide instructions on the return of all drug supplies. Under instructions from the Sponsor the investigator or designee may destroy unused or partially used study drug provided the investigator retains sufficient records of the destruction of the study drug. A final inventory of the total amount of drug received at each study site against the amount used and returned must be recorded in the Test Article Summary Inventory Record (TASIR) or equivalent document.
Inventory records must be readily available for inspection by the study monitor and/or auditor, and open to government inspection at any time.

Prior and Concomitant Medications
All prior medication taken by the subject 14 days prior to treatment intervention and all concomitant therapy taken by the subject during the study are to be recorded on the eCRF. Chemotherapeutic agents used for any chemotherapy regimen within 30 days of the first day of dosing will be recorded on the eCRF. The identity of the therapy, the dates started and stopped (or notation of "continuing" if that is the case), and the reason for use must be recorded. The use of any concomitant medication must relate to an AE or the subject's medical history.
Patients receiving other antifungal agents as prophylactic therapy must discontinue these treatments prior to study drug administration. to use. No other topical or oral antifungal agents may be used as prophylactic treatments (eg, clotrimazole as prophylaxis in patients with mucositis). Table 3 lists the other prohibited medications and recommended washout periods to be observed prior to initiation of POS oral. The washout period for POS after discontinuation of POS oral is approximately 7 days. Subjects should be monitored for untoward reactions if any of the prohibited medications are administered during the POS washout period (7 days post treatment) and AEs related to potential drug interactions should be reported in the eCRF.
The following recommendations should be followed for other concurrent medications: Ciclosporin: In heart transplant patients on stable doses of ciclosporin, POS 200 mg once daily increased ciclosporin concentrations requiring dose reductions of up to 29%. Cases of elevated ciclosporin levels resulting in SAEs, including nephrotoxicity were reported in clinical efficacy studies. Monitoring of ciclosporin blood levels should be performed upon initiation, during coadministration, and upon discontinuation of POS treatment, with adjustment of ciclosporin doses as necessary.
Tacrolimus: POS increased C max and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % and 358 %, respectively. Clinically significant interactions resulting in hospitalization and/or POS discontinuation were reported in clinical efficacy studies. When initiating POS treatment in patients already receiving tacrolimus, the dose of tacrolimus dose should be reduced (eg, to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during coadministration, and upon discontinuation of POS, and the dose of tacrolimus should be adjusted as necessary.
Sirolimus: The co-administration of POS and sirolimus is not recommended. However, if it is required, when initiating therapy in patients already taking sirolimus, the dose of sirolimus should be reduced (eg, to about 1/10 of the current dose) with frequent monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be performed upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses reduced accordingly.
Antiretroviral Agents: As HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are CYP3A4 substrates, it is expected that POS will increase plasma levels of these antiretroviral agents. Patients should be carefully monitored for any occurrence of toxicity during the coadministration of POS and these agents. Note that coadministration of POS with atazanavir, efavirenz, fosamprenavir, or ritonavir is not permitted during the treatment phase of the study ( Digoxin: Administration of other azoles has been associated with increases in digoxin levels. Therefore, POS may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing POS treatment.
Sulfonylureas: Glucose concentrations decreased in some healthy subjects when glipizide was coadministered with POS. Monitoring of glucose concentrations is recommended in diabetic patients.

Medications Prohibited Prior to Study Drug Administration and During the Study Treatment Phase
The medications prohibited prior to study drug administration and during the treatment phase of the study are listed in Table 3

Medications Allowed During the Study
The medications allowed during the study are presented in Table 4. Medications prohibited during this study are summarized in Table 3: Clinical and/or QTc monitoring is recommended when the study drug is coadministered with one of the following drugs that have reported a potential risk of torsades de pointes: antiarrhythmics (amiodarone, dofetilide, procainamide, sotalol), chlorpromazine, clarithromycin, domperidone, droperidol, levomethadyl, mesoridazine, methadone, erythromycin, sparfloxacin, or thioridazine.
The drugs listed below are permitted, although their efficacy and safety should be clinically monitored and/or serum levels followed with appropriate dosage adjustments as necessary at the initiation of study drug, periodically during treatment, and after discontinuation of study drug: POS interferes with the hepatic clearance of triazolam and midazolam, and thus, may enhance the sedative effects of these agents. Therefore, these agents are not allowed unless monitoring is provided for excessive sedation.
Use of omeprazole or other proton-pump inhibitors or cimetidine for stress ulcer prophylaxis or treatment are not permitted during the Treatment Phase of the study.

Diet
Meals (breakfast, lunch, dinner and snacks) will be of similar nutritional composition for all subjects/groups, with the possible exception of infants being fed formula or breast-milk exclusively, and will be provided around the same time each day.
When meal and blood draw times coincide, blood will be drawn BEFORE the meal is provided.
Water may be consumed ad libitum.
POS oral will be administered with food or oral nutritional supplement containing fat calories (eg, Ensure, Sustacal, etc). POS oral doses will be administered within approximately 10 minutes after completion of the meal or oral nutritional supplement.

Tobacco
The enrollment of patients who are smokers is not expected to occur in this trial.

Alcohol
The enrollment of subjects who consume alcohol is not expected to occur in this trial.

Exercise
Subjects should refrain from rigorous exercise or physical exertion 48 hours prior to entering into the study and during the study.

Other Restrictions
None.

Procedures for Monitoring Subject Compliance
At all protocol-specified visits, the investigator or qualified designee is to note in the administration record and in the appropriate section of the eCRF whether treatment had been taken per protocol in the preceding interval. If not, the date(s) and reason for each deviation must be recorded. Space is provided on the eCRF, for explanatory comments. In addition, the study staff will maintain an ongoing record of the dispensing, administration and the return (if appropriate) of all study medication for each subject on the TAAL or equivalent document that will be verified by the Sponsor's study monitor.

Blood Sampling
For subjects weighing >6.5 kg, PK samples will be drawn on Days 1 and 7, immediately prior to oral administration of POS, and at approximately 3, 5, 8, and 12 hours from the time of oral administration of the morning dose for BID dosing. If TID dosing is required, the 12-hour time point will not be collected, and the 8-hour sample for TID must be taken prior to the next dose. The same criteria apply to subjects in Age Group 3 weighing <6.5 kg with the notable exception that no Day 1 PK samples will be collected for these subjects.
In all subjects, POS C min or trough samples (immediately prior to dosing) will be obtained on Days 3, 5, 8, 14 and 28, or within 24 hours after the last dose of study drug for early discontinuation. In addition, laboratory blood tests will be performed at Screening and Baseline and throughout the treatment period on Days 1, 3, 5, 7, 14, 21, and 28 or last day of study drug administration, and at 9 2 days of follow-up to assess the safety and tolerance of POS.

Study Procedures
An overview of the study is provided in the Study Design Diagram in Section 2. • Explain Study and Obtain Written Informed Consent: Screening.
The investigator or qualified designee will explain the study and all study requirements to the subject and the subject's parent(s) or legal guardian, answer all questions, and obtain written informed consent from the subject's parent(s) or legal guardian before performing any study-related procedure. A copy of the informed consent will be given to the subject and/or the subject's parent(s) or legal guardian. Assent will be obtained from minors according to institutional practices.
Subjects are to be assigned a screening number when the informed consent is signed.
The inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the study.
The demographic profile will include the subject's date of birth, age, ethnicity, gender, and race.
A detailed medical history will be obtained by the investigator or qualified designee. Subject history should include information on family history and personal history, history of diseases including past history of hepatitis, allergies or reactions to medications and food, seizures, and previous surgery, trauma, syncope, arrhythmias. Any clinically relevant changes found at any time during the study will be recorded as adverse events. • Physical Examination: Screening, Baseline.
The principal investigator or designee will perform a physical exam at the times indicated in Section 2.2, Study Flow Chart. Any medical conditions found at the Screening and Baseline exams will be recorded on the eCRF in the Medical History module. The status of the condition will be evaluated as "resolved", "stable" or "unstable". Any unstable medical condition will require a comment. An exacerbation of a pre-existing condition or any new finding that occurs during the study will be captured as an adverse event and recorded in the Adverse Event module of the eCRF.
• Body Weight (kg) Without Shoes: Baseline, Day 28 or End of Treatment.
Body weight at each required visit should be performed on the same scale for the same individual. Measurements should be recorded to the nearest kg.
Height measurements will be recorded to the nearest cm.
• Vital Signs: Screening, Baseline, Days 1, 3, 5, 7, 14, 21, 28 or End of Treatment, Last Study Visit. The pretreatment vital signs will be considered the Baseline values. Vital signs will be obtained by the principal investigator or designee. Subjects will be in a supine position for at least 3 minutes. Systolic and diastolic blood pressure (mm Hg), pulse rate (bpm) and body temperature (C or F) will be obtained according to local standard procedure and will be recorded. If the scheduled time for vital sign measurements coincides with a blood collection, the vital signs should be performed prior to the blood collection, or at least 5 minutes afterwards. This same timing for obtaining the vital signs (before or after the blood collection) should be used for all vital sign measurements. Body temperature obtained within one hour of blood product transfusions should not be included on the eCRF. On the required days, the maximum daily temperature (outside of blood product transfusions) will be collected and recorded on the eCRF.
Two baseline ECGs must be performed at least 5 minutes apart at Baseline Visit for purposes of protocol eligibility. Prior to study drug administration, all ECGs should be reviewed for clinically significant abnormalities and reported as normal or with findings that are not clinically significant. ECGs should also be performed as clinically indicated for the evaluation of AEs. ECGs performed after the Baseline Visit should be done at the same time of day (AM or PM) that baseline ECGs were performed and prior to a meal. A standard 12-lead ECG, reporting ventricular rate, PR, QRS, QT, and QTc intervals, will be performed using equipment provided by the Sponsor for this purpose. Any clinically significant abnormality must be followed until stabilization or return to Baseline. ) after repeated ECG for confirmation a cardiology consultation is to be requested to determine possible etiologies in addition to or other than study drug should also be performed at the same time (eg, review of other concomitant drugs, and determination of serum Mg, Ca, and K levels). The investigator will determine if discontinuation of study drug is warranted after clinical examination of the subject and pertinent laboratory evaluation, and discussion of the case with the Sponsor's project physician. ECGs performed will be transferred to a blinded third-party for an evaluation of the QT, QTc (Fridericia and Bazett), PR, and QRS intervals and ventricular rate, as well as an overall clinical interpretation. The final results of the third-party analysis will be considered the definitive ECG data and will be the only ECG data used in the analysis.
Note: When the collection of vital signs, ECGs, and PK samples coincide, the blood samples for PK determination (so that the PK samples are collected on time) should be collected first, then the vital signs, and then the ECG. It is preferred that the ECG be performed at the same time each day (eg, morning) to reduce diurnal variation. For screening and unscheduled ECGs, a ventricular rate of 60 through the upper limit by age will be considered normal sinus rhythm, a rate <60 bpm will be considered sinus bradycardia, and a rate 10% above the age specific limit will be considered sinus tachycardia.
A chest radiograph will be performed as clinically indicated to evaluate for fungal infection.
• Each subject and/or the subject's parent(s) or legal guardian will keep a diary of food consumed with study drug administration throughout the treatment period. For bottle fed infants, the number of feedings, timing and amount consumed should be recorded. For infants who are breastfed exclusively, the timing of each feeding should be recorded. A dietitian/knowledgeable healthcare provider will analyze the information in the food intake diary to summarize the quantity (full intake, partial diet, or fasting) of food consumed and to estimate the percent of fat consumed by the subject with administration of each dose. This information will be entered by study center personnel into the eCRF module.
• Survival Assessment: Any day from Days 60 to 70.
Survival assessment, if the subject is alive or dead, will be performed any day from Days 60 to 70. If the subject dies, the date of death will be recorded.

Pharmacokinetics
Plasma SCH 56592 concentration data will be used to estimate the following primary PK variables for the determination of bioavailability comparisons: C min -POS trough level immediately before a subject receives the dose on the day specified in the protocol. CL/F -Total apparent body clearance at the steady state.
The current blood samples schedule is an optimized schedule based on the adult steady-state PK data. If all blood samples can be collected at steady-state as scheduled (Day 7), the steady-state AUC will be calculated using the noncompartmental trapezoidal method. (16) If more than one blood sample will be available for a patient, the concentration values will be averaged (C avg ). If data allow a calculation of AUC using a noncompartmental trapezoidal method, (16) the C avg will also be calculated by dividing the AUC with dosing interval.

Specification of Safety Variables
Safety variables to be assessed include: AEs, hematology and blood chemistry, vital signs, physical examinations, and ECGs. The key AEs to be evaluated for this study are treatment-emergent, treatment-related cardiac events, hepatic events, pulmonary embolism, and thrombocytopenia. Specifically, clinical laboratory tests, changes in vital signs, and changes from baseline ECG readings (QT/QTc intervals) will also be measured to determine the safety and tolerability of POS in each dose group.

Assessment and Reporting of Adverse Events
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.
Additionally, any event that is associated, or observed in conjunction, with a product overdose (whether accidental or intentional) or a product abuse and/or withdrawal is also considered an AE.

All AEs must be recorded in the subject's medical records and on the eCRF.
The onset and end dates, severity and relationship to study drug will be recorded for each AE. The severity of the AE will be assessed according to specific guidelines (Section 7.7.2.2.1, Assessment of Adverse Event Severity and Relationship to Treatment). Any action or outcome (eg, hospitalization, discontinuation of therapy, etc) will also be recorded for each AE.
Subjects and/or the subject's legal guardian will be questioned and/or examined by the investigator or a qualified designee for evidence of AEs. The questioning of subjects with regard to the possible occurrence of AEs will be generalized such as, "How have you been feeling since your last visit?" The presence or absence of specific AEs should not be elicited from subjects.

Assessment of Adverse Event Severity and Relationship to Treatment
Where the determination of AE severity rests on medical judgment, the determination of severity must be made with the appropriate involvement of a medically-qualified investigator.
The National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading system will be used for grading severity of AEs (see http://ctep.cancer.gov/reporting/ctc.html). The site will obtain the current version of the grading system, confirm the version with the study monitor and make a copy available to the Institutional Review Board (IRB)/Ethics Committee (EC). For AEs not covered by this grading system, the following definitions will be used: Mild: awareness of sign, symptom, or event, but easily tolerated; Moderate: discomfort enough to cause interference with usual activity and may warrant intervention; Severe: incapacitating with inability to do usual activities or significantly affects clinical status, and warrants intervention; Life-Threatening: immediate risk of death.
A medically-qualified investigator must assess the relationship of any AE to the use of study drug, based on available information, using the following guidelines: Unlikely related: no temporal association, or the cause of the event has been identified, or the drug, biological, or device cannot be implicated; Probably related: temporal association, other etiologies are possible, but unlikely.
The expectedness of an adverse reaction shall be determined in each country according to the specified reference document containing safety information. The reference document containing safety information for the investigational medicinal product (IMP), Posaconazole, Aqueous Oral Suspension, in this current study is to be the most recent Investigator's Brochure for Posaconazole, SCH 56592, Aqueous Injectable Suspension, Aqueous Oral Suspension. (8)

Monitoring Adverse Events
Subjects having AEs will be monitored with relevant clinical assessments and laboratory tests, as determined by the investigator. The investigator or qualified designee is expected to report ongoing AEs at completion of the clinical study to the primary care physician who will determine the need for and provide standard medical care.
Any actions taken and follow-up results must be recorded either on the appropriate page of the eCRF or in a follow-up letter to the Sponsor, as well as in the subject's source documentation. Follow-up laboratory results should be filed with the subject's source documentation.
For all AEs that require the subject to be discontinued from the study, relevant clinical assessments and laboratory tests will be repeated as clinically appropriate, until final resolution or stabilization of the event(s).
Adverse event reporting will be conducted as follows:

• Minor or Routine Surgical Procedures
All minor surgical procedures (unless pre-planned as part of routine care, eg, Hickman catheter placement) and the reason for the procedure are AEs. (For example, removal of a Hickman catheter for thrombosis after study drug has been given would be reported as an AE, ie, incision and drainage of abscess requiring admission to the hospital would be indicated as an SAE with outcomes of hospitalization and additional therapy.)

• Body Weight
Greater than 10% change in body weight (gain or loss) from Baseline will be considered an AE unless an increase in body weight is predicted based on standard growth charts applicable to the study center population.

Grade 4 Adverse Events
The following guidelines will be used regarding continuation of treatment: • If considered probably related to study drug, subject will be discontinued from treatment.
• If considered possibly related to study drug: the subject will be discontinued from treatment, except in the case of AEs for which a relationship to the primary disease and/or other concomitant drugs is equally likely. In these cases, a decision to discontinue study drug or interrupt study drug will be made by the investigator, in consultation with the project physician or designee. If the AE again worsens to Grade 4 after study drug has been reintroduced, the subject must be discontinued from treatment.
• If considered unlikely to be related to study drug: study drug may be continued at the discretion of the investigator, in consultation with the project physician or designee.

Grade 3 Adverse Events
Outcomes for Grade 3 AEs include the following: • If a subject experiences a Grade 3 AE considered at least possibly or probably related to study drug, a decision to continue, interrupt or discontinue study drug will be made by the investigator (in consultation with project physician or designee), taking into account the event severity, clinical significance, treatment options, and likelihood of relationship to study drug versus underlying disease and/or other concomitant drugs. • If a subject experiences a Grade 3 AE considered unlikely to be related to study drug, study drug may be continued.

Less Severe Adverse Events
Interruption or discontinuation of study drug may be appropriate in some cases for less severe AEs, which are medically significant. In such cases, the investigator should consult with the project physician or designee to decide the most appropriate course of action with regard to dosing.

Known Adverse Events Relating to the Underlying Clinical Condition
The following AEs are expected with myelodysplastic syndromes and their treatment: pancytopenia (leukopenia, anemia, and/or thrombocytopenia); manifestations of anemia such as pallor, fatigue, and dyspnea on exertion; manifestations of thrombocytopenia such as petechiae, easy bruising, epistaxis, gingival bleeding, or prolonged bleeding from trauma sites; hepatomegaly, splenomegaly, bone pain, elevated lactate dehydrogenase (LDH) serum levels, and increased uric acid levels. Other manifestations may be pathognomonic of specific primary diagnoses. Alopecia and mucositis are expected AEs with most chemotherapeutic regimens. Any AE which is worse than expected with the primary disease or its treatment (ie, greater severity or more prolonged in duration) should be reported as an AE in the eCRF. All expected Grade 4 AEs, other than alopecia, will also be reported in the eCRF and may require reporting as an SAE.
Infectious complications are common and expected during the course of the primary disease, and are considered AEs.

Known Potential Toxicities of Study Drug
Clinical studies show that POS demonstrates a favorable safety profile in its oral formulation and appears to be similar to FLU in the cumulative experience from randomized controlled clinical trials in treatment and prophylaxis. The anticipated side effects from POS (treatment-related, treatment-emergent adverse events) are gastrointestinal events (nausea, vomiting, abdominal pain), hepatic events (including asymptomatic elevations in transaminases and/or bilirubin), headache, and asthenia. These side effects are anticipated to be mild and self limited with conservative medical therapy. Refer to the Investigator's Brochure for additional information on AEs observed to date. (8) The AEs mentioned under this section still need to be recorded in the subject's medical records and on the eCRF regardless of causality.

Definition of Serious Adverse Events
A serious adverse event (SAE) is any adverse drug or biologic or device experience occurring at any dose that results in any of the following outcomes: • death; • life-threatening AE (ie, one that places the subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurs); • persistent or significant disability/incapacity; • requires in-patient hospitalization (ie, admission), or prolongs hospitalization; • congenital anomaly or birth defect.
Additionally, important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the development of drug dependency or drug abuse.
All SAEs, whether or not deemed drug-related or expected, must be reported by the investigator or qualified designee to the Sponsor's designated safety/compliance officer within 1 working day of first becoming aware of the event. If the report is given to the Sponsor via telephone rather than in writing on the form designated for SAE reporting, a full description of the event and any sequelae, including the investigator-determined causality to study drug must be provided, so that the appropriate written report can be completed by the designated Sponsor contact. SAEs that occur at any time after the inclusion of the subject in the study up to 30 days after the subject completes study treatment or discontinues the study must be reported. In the specific circumstance of screen failures, SAEs must be collected from the time of consent signing until the subject is considered a screen failure.
Reports of all SAEs must be communicated as soon as possible to the appropriate Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and/or reported in accordance with local laws and regulations.

Reporting of Subject Death
The death of any subject after enrollment or within 30 days after the subject completes study treatment or discontinues the study regardless of the cause, must be reported by the investigator or qualified designee to the Sponsor's designated safety/compliance officer within 1 working day of first becoming aware of the death. If the report is given via telephone rather than in writing on the form designated for SAE reporting, a full description of the circumstances, including the investigator-determined causality to study drug must be provided, so that the appropriate written report can be completed by the designated Sponsor contact.
If an autopsy is performed, the report must be provided to the Sponsor.
Reports of all deaths, must be communicated as soon as possible to the appropriate IRB or IEC and/or reported in accordance with local law and regulations.

Reporting of Pregnancies
Although not considered an SAE (unless an event occurs with a serious outcome), pregnancy information on clinical study subjects is collected by the Sponsor's Drug Safety Surveillance (DSS) department. If a female subject or the female partner of a male subject becomes pregnant during the course of the study, the investigator or qualified designee must contact the Sponsor's designated safety/compliance officer within 5 working days of the investigator or qualified designee first becoming aware of the pregnancy. If an SAE occurs in conjunction with the pregnancy, then the reporting time frame for an SAE (1 working day) must be met. The Sponsor's representative will provide instructions on how to collect pregnancy information. Follow-up information on the outcome of the pregnancy should also be forwarded to the Sponsor.

Preplanned Hospitalizations or Procedures
During the study, if a subject has a hospitalization or procedure (eg, chemotherapy, placement of central catheter, elective surgery) that was scheduled prior to the subject entering the study (ie, before the subject signed the informed consent) for an event/condition that occurred before the study, the hospitalization is considered a therapeutic intervention and not the result of an SAE. However, if the event/condition worsens during the study, it must be reported as an AE (or SAE, if the event/condition results in a serious outcome such as hospitalization).

Reports of Overdose
An overdose of POS is any dose more than 1600 mg orally per day.
Information on overdoses in clinical subjects is collected by the Sponsor's DSS department. Should a subject experience an overdose during the course of the study (whether symptomatic or not), the investigator or qualified designee must contact the Sponsor's designated safety/compliance officer, within 5 working days of the investigator or qualified designee first becoming aware of the overdose. Followup information on the outcome of the overdose should be forwarded to the Sponsor.
Any event associated with, or observed in conjunction with, a product overdose (whether accidental or intentional) or a product abuse and/or withdrawal is considered an AE and should be reported as such (Section 7.7.2.2). If an SAE occurs in conjunction with the overdose, then the reporting time frame for an SAE (1 working day) must be met. The Sponsor's representative will provide instructions on how to collect this information.

Protocol-Specific Exceptions to SAE Reporting to Drug Safety Surveillance
The following will not be considered SAEs: 1. An event that results in hospitalization or prolongs an existing hospitalization will not be considered a serious adverse event if the only reason for the hospitalization was: a. administration of chemotherapy b. transfusion of blood products c. administration of study procedures d. placement of a permanent intravenous catheter e. hospice placement for terminal care f. outpatient hospitalization for procedures such as elective day surgery or hospitalization due to convenience purposes (eg, transportation difficulties) 2. Any Grade 3 or 4 leukopenia, absolute neutropenia, or thrombocytopenia (regardless of baseline value) will not be considered a serious adverse event, even in the event of medical intervention to prevent medically significant sequelae. 3. Any Grade 1, 2, or 3 decrease in hemoglobin will not be considered a serious adverse event.
If an abnormal laboratory value included in item numbers 2 or 3 resulted in a clinical event, then the clinical event and not the abnormal laboratory value must be recorded as an AE in the eCRF. This clinical event must be reviewed to determine if it meets the criteria for an SAE.

Reporting of Investigational Medicinal Product Quality Complaints
Any defect or possible defect in an investigational medicinal product (defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial) must be reported by the investigator or qualified designee to the Sponsor's designated safety coordinator within 1 working day of first becoming aware of the possible defect. This report to the Sponsor may be made by telephone or by faxing the Research and Development / Commercialization Quality (RCQ) Clinical Supply Complaint GCP Inquiry Form to the designated Sponsor representative. The product and packaging components in question, if available, must be stored in a secure area under specified storage conditions until it is determined whether the product is required to be returned for investigation of the defect. If the product complaint is associated with an SAE, the SAE must be reported separately in accordance with the protocol, and the SAE report should mention the product quality complaint.

Data Monitoring Committee
The safety of subjects in this current trial will be monitored on an ongoing basis by the Sponsor and by an external Data Monitoring Committee.

STATISTICAL AND ANALYTICAL PLANS
Approximately 96 PK-evaluable subjects (12 subjects each in Age Groups 1, 2, and 3 for Dose Groups 1 and 2 plus 12 subjects each in Age Groups 1 and 2 for Dose Group 3) are expected to be enrolled.

Data Sets
The PK analysis will only include subjects who received at least one dose of drug. All subjects who received at least one dose of the drug will be included in the safety analyses.

Demographic and Other Baseline Characteristics
Demographic variables (eg, sex, race, age, weight) will be listed and summarized using descriptive statistics for the entire study population and for each treatment.

Pharmacokinetic Parameters
Single dose and multiple dose plasma concentrations and derived PK parameters for POS will be listed and summarized by dose and age group using descriptive statistics.
The PK parameters, C avg (and C max and AUC if data allow), will be log transformed for statistical analyses. Point estimates and 90% confidence intervals will be provided for each age and dose level. If the confidence intervals indicate that ages do not produce a statistical difference on a PK parameter, then age groups will be pooled. To assess preliminary dose proportionality, log transformed, dose normalized C avg (and C max and AUC if data allow) will be analyzed using analysis of variance (ANOVA) extracting the effect due to treatment. Ratio estimates and 90% confidence intervals will be calculated for the differences between doses and ages (if age groups are not pooled). The steady state analysis will be conducted using available PK trough values.
Comparison of the exposure from previous experience in adults will be conducted at steady state using graphics. A comparison between adult and pediatric patients with respect to the proportion of patients with steady-state C avg greater than or equal to 500 ng/mL will also be conducted. If appropriate, comparisons between BID and TID dosing with respect to the steady-state C avg and the proportion of patients achieving exposure above 500 ng/mL will be made. Preliminary analysis will include examining the PK parameters for extreme values by reviewing the standardized ranges of deviations from the expected value derived from the model to see if any value exceeds 3. The impact of any outlier on the results of the analyses will be evaluated.

Determination of Sample Size/Power/Level of Significance
The planned maximum sample size is 96 PK-evaluable subjects (12 subjects each in Age Groups 1, 2, and 3 for Dose Groups 1 and 2 plus 12 subjects each in Age Groups 1 and 2 for Dose Group 3). With a goal of achieving a C avg in the targeted (500 ng/mL-2500 ng/mL) range in ~90% of subjects, a dose may be considered a success from a statistical point of view if it is observed that at least 10 out of 12 subjects (≥83%) fall within the range for a particular age group. The probability of observing 83% or higher is 89%, 74%, or 56% if the true probability of being within the range is 90%, 85%, or 80%, respectively.

Interim Analysis
Statistical analysis may be conducted after completion of each group as well as those analyses specified in Section 2.1.1.
Importantly, a PK and safety analysis of all available TID data across age groups will be performed after Age Group 2 Dose Group 3 completes enrollment of 12 PKevaluable subjects.

Other Analyses
Not applicable.

Independent Ethics Committee or Institutional Review Board
Prior to initiation of the trial at any site, the trial, including the protocol, informed consent, and other trial documents must be approved by an appropriate Institutional Review Board (IRB) or Independent Ethics Committee (IEC). The IRB/IEC must be constituted according to applicable regulatory requirements. As appropriate, amendments to the protocol must also be approved by the IRBs/IECs before implementation at the sites. The IRB/IEC approval should be obtained in writing, clearly identifying the trial, the documents reviewed (including informed consent), and the date of the review. The trial as described in the protocol (or amendment), informed consent, and other trial documentation may be implemented only after all the necessary approvals have been obtained and the Sponsor has confirmed that it is acceptable for the investigator to do so.
In the event that the IRB/IEC requires changes in the protocol, the Sponsor shall be advised and must approve the changes prior to implementation. The investigator shall not modify the study described in the protocol once finalized and after approval by the IRB/IEC without the prior written approval of Sponsor.
In countries where the investigator submits the study protocol and statement of informed consent to the IRB/IEC, the investigator or qualified designee will forward the approvals to the Sponsor.

Subject Information and Consent
The details of the protocol must be discussed with each potential subject and/or the subject's parent(s) or legal guardian, and written informed consent must be obtained for all subjects before any study-related procedure is performed. In obtaining informed consent, the information must be provided in language and terms understandable to the subject. The subject, or the subject's legal representative, must give their written consent to participate in the trial. The signed and dated consent form itself must be retained by the investigator as part of the trial records. A copy of the signed and dated consent form must be given to the subject. The consent form must include all of the required elements of informed consent in accordance with ICH Guidelines E6 and local laws. In addition, the Sponsor specifically requests that the consent form identify it as the Sponsor and state that use of the drug is experimental and the side effects of the drug are not completely known. The consent form must be approved by the appropriate IRB/IEC and Sponsor before study initiation at a study site. Any subsequent changes to the approved informed consent form must be reviewed and approved by the appropriate IRB/IEC and Sponsor before implementation.

Protocol-Related Regulatory and Ethical Considerations/Issues
None.

Reporting to Sponsor
The investigator will ensure that there are sufficient time, staff, and facilities available for the duration of the trial to conduct and record the trial as described in the protocol and according to all applicable guidances, laws, and regulations.
Any records or documents used as the source of information in the eCRF (called the "subject source data") are to be retained for review by authorized representatives of the Sponsor or a regulatory agency.
The investigator must maintain records and data during the trial in compliance with all applicable legal and regulatory requirements. The investigator is to provide subject data on completed eCRFs, according to the Sponsor's instructions and compliant with GCP practices. eCRFs and the electronic database from the trial are the exclusive property of Sponsor.
All data collection forms, be they CRFs, electronic Case Report Forms (eCRF), or other Electronic Data Capture (EDC) screens, should be completed as soon as possible after the evaluation has occurred. All dates appearing on the Sponsor's subject data collection forms for laboratory tests, cultures, and other data collected, must be the dates on which the specimens were obtained, or the procedures performed. A CRF must be completed for all subjects as per Section 7.2, Participation in and Completion of the Study. The Sponsor must not collect subject names, initials, or other personal information that is beyond the scope of the trial from any subject. Subjects are not to be identified by name or initials on the CRF or any trial documents. The only acceptable identification for a subject that may appear on a CRF or trial document is the unique subject identification number. The investigator must maintain contact information for each participant so that all can be quickly contacted by the investigator, if necessary.
A CRF or screening log with a minimum of the following information shall be completed for subjects who fail screening: (1) demographics, (2) subject status, (3) reason for screen failure, and (4) serious adverse events. Data are to be collected from the time the informed consent form is signed until the subject is determined to have failed screening.
All entries into CRFs are the responsibility of the investigator and must be completed by the investigator or a qualified designee. The investigator will acknowledge in writing that he/she has verified the accuracy of the recorded data.

Rights to Publish by the Investigator
The investigator has the right to publish or publicly present the results of the study in accordance with this Section 9.3 of the protocol. In the event that the protocol is a part of a multi-site study, it is understood that it is the intent of the Sponsor and the investigator to initially only publish or present the study results together with the other sites, unless specific written permission is obtained in advance from the Sponsor to publish separate results. The Sponsor shall advise as to the implications of timing of any publication in the event clinical trials are still in progress at sites other than the investigator's site.
The investigator agrees not to publish or publicly present any interim results of the study without the prior written consent of the Sponsor. The investigator further agrees to provide to the Sponsor 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication (including, without limitation, slides and texts of oral or other public presentations and texts of any transmission through any electronic media, eg, any computer access system such as the Internet, World Wide Web, etc) that report any results of the study. The Sponsor shall have the right to review and comment with respect to publications, abstracts, slides, and manuscripts and the right to review and comment on the data analysis and presentation with regard to the following concerns: 1. proprietary information that is protected by the provisions contained in Section 9.3.2; 2. the accuracy of the information contained in the publication; and 3. to ensure that the presentation is fairly balanced and in compliance with FDA regulations.
If the parties disagree concerning the appropriateness of the data analysis and presentation, and/or confidentiality of the Sponsor's confidential information, investigator agrees to meet with the Sponsor's representatives at the clinical study site or as otherwise agreed, prior to submission for publication, for the purpose of making good faith efforts to discuss and resolve any such issues or disagreement.

Use of Proprietary or Confidential Information in a Publication
No publication or manuscript shall contain any trade secret information of the Sponsor or any proprietary or confidential information of the Sponsor and shall be confined to new discoveries and interpretations of scientific fact. If the Sponsor believes there is patentable subject matter contained in any publication or manuscript submitted for review, the Sponsor shall promptly identify such subject matter to investigator. If Sponsor requests and at Sponsor's expense, investigator shall use its best efforts to assist Sponsor to file a patent application covering such subject matter with the USA Patent and Trademark Office or through the Patent Cooperation Treaty prior to any publication.

Use of Trial Information in a Publication
Investigator is granted the right subject to the provisions of this protocol to use the results of all work provided by investigator under this protocol, including but not limited to, the results of tests and any raw data and statistical data generated for investigator's own teaching, research, and publication purposes only. Investigator/Institution agrees, on behalf of itself and its employees, officers, trustees, and agents, not to cause said results to be knowingly used for any commercial purpose whatsoever except as authorized by the Sponsor in writing.

Authorship of Publications
Authors of publications must meet the International Committee of Medical Journal Editors (ICMJE) guidelines for authorship and must satisfy the 3 criteria that follow: 1. Authors must make substantial contributions to the conception and design of the trial, acquisition of data, or analysis of data and interpretation of results; 2. Authors must draft the publication or, during draft review, provide contributions (data analysis, interpretation, or other important intellectual content) leading to significant revision of the manuscript with agreement by the other authors; 3. Authors must provide written approval of the final draft version of the publication prior to submission.
All contributors who do not meet the 3 criteria for authorship should be listed in an acknowledgments section within the publication, if allowed by the journal, per the ICMJE guidelines for acknowledgment.

Shipping of Hazardous or Dangerous Goods
It is the responsibility of the investigator to ensure that all staff personnel who will be handling, packaging, and/or shipping clinical specimens or any other hazardous or dangerous goods act in conformance with International Air Transport Association (IATA) regulations relating to the handling and shipping of hazardous or dangerous goods.

Trial Documents and Records Retention
During the trial and after termination of the trial -including after early termination of the trial -the investigator must maintain copies of all documents and records relating to the conduct of the trial. This documentation includes, but is not limited to, protocols, CRFs, advertising for subject participation, adverse event reports, subject source data, correspondence with health authorities and IRBs/IECs, consent forms, investigator's curricula vitae/biosketch, monitor visit logs, laboratory reference ranges, and laboratory certification or quality control procedures and laboratory director curriculum vitae. Subject files and other source data must be kept for the maximum period of time permitted by the hospital, institution or private practice, or as specified below. The study monitor must be consulted if the investigator wishes to assign the files to someone else, remove them to another location, or is unable to retain them for the specified period.
The investigator must retain trial records for the amount of time specified by applicable laws and regulations. At a minimum, trial records must be retained for the 1. The ICH Guidelines specify that records must be retained for a minimum of 2 years after a marketing application for the indication is approved (or not approved) or 2 years after notifying the appropriate regulatory agency that an investigation is discontinued. 2. The EU GCP Directive specifies that trial records must be retained for 5 years after the completion of the trial.
All trial documents shall be made available if required by relevant health authorities. The investigator should consult with the study monitor prior to discarding trial and/or subject files.
Sponsor will retain all Sponsor-required documentation pertaining to the trial for the lifetime of the product. Archived data may be held on microfiche or electronic record, provided that a back-up exists and that a paper copy can be obtained from it, if required.

Sponsor
The Sponsor of this study is indicated in Section 1, Title Page.

Selecting Investigators
Only investigators qualified by training and experience to perform a clinical investigation with POS are selected. The Sponsor will contact and select all investigators or coinvestigators (ie, the legally responsible party[ies] at each study site), who, in turn, will select their staff.

Financial Disclosure Requirement
In connection with the clinical study described in the protocol, the investigator certifies that, if asked, the investigator will read and answer the Clinical Investigator Financial Certification Form truthfully and to the best of investigator's ability.
Investigator also certifies that, if asked, the investigator will have any other applicable party(ies) (eg, subinvestigators) read and answer the Clinical Investigator Financial Certification Form as a condition of their participation in the study.
If the financial interests reported on the Clinical Investigator Financial Certification Form change during the course of the study or within 1 year after the last subject has completed the study as specified in the protocol, the investigator and the other applicable party(ies) are obligated to inform the Sponsor of such financial change.

Clinical Study Report Coordinating Investigator
A clinical study report (CSR) will be prepared by the Sponsor or its qualified designee to describe the results of the study. One of the investigators shall be selected by the Sponsor to review the CSR and provide approval of the final CSR in writing. The investigator chosen to review and approve the CSR is to be called the CSR Coordinating Investigator. A second investigator shall be selected as the Alternate CSR Coordinating Investigator. The Alternate CSR Coordinating Investigator is to review and approve the CSR should the first CSR Coordinating Investigator be unable to do so. The Sponsor is to select the CSR Coordinating Investigator and Alternate CSR Coordinating Investigator from the investigators using the following criteria: • Expertise in the area of PK in pediatrics; • Active participation during the trial; and/or • Active participation during the analysis of the results.

Central Organizations
Central organizations to be used in the conduct of this trial are provided on the Contact List. The POS oral dosing will be administered using the Sponsor-supplied 1-mL, 3-mL, or 10-mL oral dosing syringe.
As this is an open label study, use one bottle for one subject from the bulk supply.
The bulk supply will be packaged with 6 bottles per box. Each bottle will be used as an individual treatment bottle. As of 25-Jan-2013, a total of 81 subjects, 2 to <18 years of age, were enrolled and treated in the study P03579. A review of the safety and PK data from the first two dose groups was performed by the external Data Monitoring Committee and the Sponsor. No safety concerns were identified. The POS PK exposure target for the study, ~90% of subjects with POS steady-state C avg in the range of 500 ng/mL to 2500 ng/mL has not been achieved at either dose level. Summaries of the PK and safety data are provided in the below tables.

Posaconazole Oral Treatment Preparation and Administration
The preliminary PK results of POS plasma concentrations in P03579 subjects from Age Group 1 (2 to <7 years of age) Dose Groups 1 and 2, and Age Group 2 (7 to <18 years of age) Dose Groups 1 and 2, are shown in Table 5. An overview of the available safety data (through 25-Jan-2013) from P03579 is provided in Table 6.            Based on available safety data (through 25-Jan-2013), a summary of treatment-related TEAEs organized by MedDRA SOC is provided for P03579 in Table 8 . The most frequently (>10% of subjects) reported treatment-related TEAEs were vomiting and nausea.