Dear Pharm.D Murry,

Thank you very much for submitting your manuscript "Pharmacokinetics of Moxidectin Combined with Albendazole or Albendazole plus Diethylcarbamazine for Bancroftian Filariasis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

The Academic Editor apologizes for the delay in completing this review. In light of the challenge of finding reviewers who have experience in pharmacokinetics and LF, I elected to provide a second review, as I have experience in this area.

The responsive reviewer found considerable merit in the manuscript to the extent that the data presented are generally consistent with a conclusion that marked drug-drug interactions do not occur among the three medicines used in triple therapy for LF. However, the reviewer noted that the trial design is not entirely appropriate for a direct DDI study; although I agree, I do not feel that this distracts from the conclusions. Nonetheless, it should be ackowledged in the text. Like the responsive reviewer, I am somewhat concerned by the discrepancy in plasma half-lives observed here compared to previous reports, and this should also be addressed by the authors in the Discussion.

Lastly, the authors should deposit the raw data in an accessible database, fully anonymized, and provide that location in the text.

Like the responsive reviewer, I believe this manuscript will be a valuable addition to the literature and look forward to receipt of an appropriately revised version.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Timothy G. Geary, PhD

Guest Editor

PLOS Neglected Tropical Diseases

Cinzia Cantacessi

Section Editor

PLOS Neglected Tropical Diseases

***********************

The Academic Editor apologizes for the delay in completing this review. In light of the challenge of finding reviewers who have experience in pharmacokinetics and LF, I elected to provide a second review, as I have experience in this area.

The responsive reviewer found considerable merit in the manuscript to the extent that the data presented are generally consistent with a conclusion that marked drug-drug interactions do not occur among the three medicines used in triple therapy for LF. However, the reviewer noted that the trial design is not entirely appropriate for a direct DDI study; although I agree, I do not feel that this distracts from the conclusions. Nonetheless, it should be ackowledged in the text. Like the responsive reviewer, I am somewhat concerned by the discrepancy in plasma half-lives observed here compared to previous reports, and this should also be addressed by the authors in the Discussion.

Lastly, the authors should deposit the raw data in an accessible database, fully anonymized, and provide that location in the text.

Like the responsive reviewer, I believe this manuscript will be a valuable addition to the literature and look forward to receipt of an appropriately revised version.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objective of the study “…is to determine whether the incorporation of moxidectin (MOX) into MDA regimens for LF will alter the pharmacokinetics of co-administered drugs”. However, this is a sub study and this was not the primary objective of the clinical trial.

In terms of moxidectin’s risk of drug:drug interactions (DDIs), these were formally evaluated as part of its development by Wyeth/Pfizer, MDGH and the US FDA. Based on the metabolic pathways, transporters, and previous data with midazolam as a probe (Korth-Bradley et al, 2014), the risk of DDIs with this combination of compounds was negligible based on in silico modelling. While the paper describes data that are supportive of this position, this was not prospectively designed as a drug:drug interaction study (i.e clinical DDI studies compare substrate concentrations in the absence and presence of a perpetrator or victim drug). As such, negative findings (in terms of not identifying a DDI) from retrospective studies such as this (i.e not prospectively defined solely for the purpose of DDI evaluation) have limited value and cannot inform regulatory authorities. Recommend that the authors review FDA Guidance for Industry https://www.fda.gov/media/134581/download to help understand the deficiencies between this design and a DDI study.

A comment on how patients were selected for the pharmacokinetic sub study and how similar or different they were to the broader population in the clinical trial would also be helpful.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The pharmacokinetic results of moxidectin and ivermectin are different from previously published data - ivermectin T1/2 is 15 hours in the US FDA PI and moxidectin’s is between 20 and 40 days. Ivermectin’s T1/2 was significantly longer than published data and moxidectin’s significantly shorter. Data from doi:10.1371/journal.pntd.0010005 should be the primary comparison used in the discussion. Performance of the assays used should be commented upon - how the assays were validated should be commented on. Also, their performance (e.g. range of quantation, inter day, inter operator performance parameters should be given). The number of available samples at each time point should be noted at some place in the paper - were these analyses based on available samples or on patients with complete sets? Also, were the samples all compliant with sampling windows and if not, how many were deviant from prospectively defined windows? How close was dosing relative to food intake?

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported but there is a tendancy to overstate the value of the data. This study was not the designed by standard DDI methodologies to evaluate the question. The outlying data from this study compared to all other pharmacokinetic data on moxidectin and ivermectin warrant comment - it leads to the differences being due to disease questions or study execution/assay questions. The underlying message remains that the data do not generate concerns about the use of these agents together.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: It should be noted that DEC can result in life threatening system reactions and not just ocular reactions in onchocerciasis patients.

It should say that this is a sub study.

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The data are of value. The comments on the experiment are already noted but the authors are to be congratulated on executing this trial.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Pharm.D Murry,

We are pleased to inform you that your manuscript 'Pharmacokinetics of Moxidectin Combined with Albendazole or Albendazole plus Diethylcarbamazine for Bancroftian Filariasis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Timothy G. Geary, PhD

Guest Editor

PLOS Neglected Tropical Diseases

Cinzia Cantacessi

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

The authors have resolved the concerns expressed by the reviewer as part of the process of evaluation, and have as a result improved the clarity and quality of the manuscript. As a scientist with some expertise in this area, the Associate Editor believes that the manuscript meets the standards associated with publication in PLoS-NTDs.