Population Pharmacokinetics of Tamibarotene in Pediatric and Young Adult Patients with Recurrent or Refractory Solid Tumors

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This work reports on population pharmacokinetic modelling of tamibarotene in a small sample of paediatric patients with various cancers. The work appears to be qualitative, well conducted and well presented (of note, the wording and writing in English is very good), and seems to fill a gap in the literature, as few pharmacokinetic studies (especially in paediatrics) are available for tamibarotene.

A few but important comments should be brought to the authors' attention:

- End of the introduction part: it might be interesting to place particular emphasis on the fact that the study concerns a paediatric population (or young patients, at least).

- Part 2.1: it might be interesting to specify the galenic form of tamibarotene used orally in this study.

- Part 2.3: more information on the dosing method would be useful: which of the wavelengths allowed by the detector was used? Also, on what values was the RE% validated? Finally, was a more thorough validation of the method carried out, particularly concerning the linearity of detection over the working range and the repeatability of the method? The results of this validation would be welcome.

- lines 122-123 and 127-129 are rather unclear and should be slightly reworded for better understanding.

- line 159: it would be more accurate to say ‘22 patients’ instead of 21, as the table shows 15 + 7 patients. Also, further details on the reason for excluding this one patient would be welcome.

- Table 1: for quantitative variables, the mean and standard deviation (in addition to the median) would be interesting for estimating the dispersion of values in the group of patients.

- Table 2: similarly, the addition of the standard deviation to the mean values given would be welcome.

- End of Discussion part: when the limitations of the study are mentioned, wouldn't it be relevant to talk about the variety of cancer diseases affecting patients in this group? Could the difference in tumor type have an impact on PK? Similarly, wouldn't the large age differences between patients in the group have an impact on PK, especially at the youngest ages?

- Conclusion part: even more perspectives could be given following this work. For example, according to what organization/scheme could future PK studies be conducted?

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Editor and Authors,

It was my pleasure to review this manuscript titled "Population pharmacokinetics of tamibarotene in pediatric and young adult patients with recurrent or refractory solid tumors." by Dr. Takuya Azechi and colleagues from Japan.

This is a a phase I, open-label, multicenter, multi-institution study conducted at four medical centers in Japan conducting a on-compartmental analysis (NCA) and population pharmacokinetic (popPK) analysis to evaluate the pharmacokinetic characteristics and construct a popPK model of tamibarotene in 22 patients aged 3–30 years who were diagnosed with advanced or recurrent solid tumors, including histologically confirmed sarcomas, blastomas, germ cell tumors, and CNS tumors. The authors found  a significant influence of BSA on the clearance and distribution of tamibarotene.

This is a very interesting study which is well setup and methodological solid. It it well conducted and presented. The findings appear robust and accurate. The discussion is thorough.

I only have some minor comments which I feel when answered would allow the work to be presented in the literature. 

Comments:

1. Was a sample size calculation performed prior to the commencement of the study?

2. Was 22 or 21 patients included in the study? Line 159 says 21 while the table says 22??

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I acknowledge the modifications made by the authors.