Effects of Aprepitant on the Pharmacokinetics of Controlled-Release Oral Oxycodone in Cancer Patients

Purpose Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone. Method This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3. Results Aprepitant increased the area under the plasma concentration-time curve (AUC0–8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC0–8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1. Conclusions The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose. Trial Registration UMIN.ac.jp UMIN000003580.


Introduction
Background 2 Scientific background and explanation of rationale ✔ Introduction Theories used in designing behavioral interventions ✔ Introduction

Participants 3
Eligibility criteria for participants, including criteria at different levels in recruitment/sampling plan (e.g., cities, clinics, subjects) ✔

Methods-Patient selection criteria
Method of recruitment (e.g., referral, self-selection), including the sampling method if a systematic sampling plan was implemented ✔ Unit of assignment (the unit being assigned to study condition, e.g., individual, group, community) ✔

Methods-Study design
Method used to assign units to study conditions, including details of any restriction (e.g., blocking, stratification, minimization) ✔

Methods-Study design
Inclusion of aspects employed to help minimize potential bias induced due to non-randomization (e.g., matching) ✔

Methods-Study design
Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to study condition assignment; if so, statement regarding how the blinding was accomplished and how it was assessed.

Unit of Analysis 10
Description of the smallest unit that is being analyzed to assess intervention effects (e.g., individual, group, or community) ✔

Methods-Pharmacokinetic Analysis
If the unit of analysis differs from the unit of assignment, the analytical method used to account for this (e.g., adjusting the standard error estimates by the design effect or using multilevel analysis) ✔

Methods-Pharmacokinetic Analysis
Statistical Methods

11
Statistical methods used to compare study groups for primary methods outcome(s), including complex methods of correlated data ✔

Methods-Statistical Analysis
Statistical methods used for additional analyses, such as a subgroup analyses and adjusted analysis ✔

Methods-Statistical Analysis
Methods for imputing missing data, if used ✔ Methods-Statistical

Analysis
Statistical software or programs used ✔ Methods-Statistical

Participant flow 12
Flow of participants through each stage of the study: enrollment, assignment, allocation, and intervention exposure, follow-up, analysis (a diagram is strongly recommended) ✔ Results + Fig. 1 o Enrollment: the numbers of participants screened for eligibility, found to be eligible or not eligible, declined to be enrolled, and enrolled in the study ✔ Results + Fig. 1 o Assignment: the numbers of participants assigned to a study condition ✔ Results + Fig. 1 o Allocation and intervention exposure: the number of participants assigned to each study condition and the number of participants who received each intervention ✔ Results + Fig. 1 o Follow-up: the number of participants who completed the followup or did not complete the follow-up (i.e., lost to follow-up), by study condition ✔ Results + Fig. 1 o Analysis: the number of participants included in or excluded from the main analysis, by study condition ✔ Results + Fig. 1 Description of protocol deviations from study as planned, along with reasons ✔ Results + Fig. 1 Recruitment 13 Dates defining the periods of recruitment and follow-up ✔ Results-Patient population Baseline Data 14 Baseline demographic and clinical characteristics of participants in each study condition ✔ Results-Patient population + Table 1 Baseline characteristics for each study condition relevant to specific disease prevention research ✔ Results-Patient population + Table 1 Baseline comparisons of those lost to follow-up and those retained, overall and by study condition ✔ Results-Patient population + Table 1 Comparison between study population at baseline and target population of interest ✔ Results-Patient population + Table 1 Baseline equivalence 15 Data on study group equivalence at baseline and statistical methods used to control for baseline differences ✔ Results-Patient population + Table 1 Numbers analyzed 16 Number of participants (denominator) included in each analysis for each study condition, particularly when the denominators change for different outcomes; statement of the results in absolute numbers when feasible ✔

Resultspharmacokinetics
Indication of whether the analysis strategy was "intention to treat" or, if not, description of how non-compliers were treated in the analyses ✔

Generalizability 21
Generalizability (external validity) of the trial findings, taking into account the study population, the characteristics of the intervention, length of follow-up, incentives, compliance rates, specific sites/settings involved in the study, and other contextual issues