Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy

Round 1

Reviewer 1 Report

The authors developed and validated PBPK models for lamotrigine (LTG) and raltegravir (RTG) in pregnancy population, which is mainly metabolized by UGT. The overall organization, tables, figures, and language well communicates the study's findings. But several details were missing in the methodology and results. I would suggest that the authors make a few additions in the manuscript. These items are described below.

Key words may include UGT1A1.

The introduction could be concise to emphasize the importance of this work. It is not necessary to include all the background information for pregnancy population.

The following articles needs to be included in the validation for lamotrigine.

Petrenaite V, et al. UGT polymorphisms and lamotrigine clearance during pregnancy. Epilepsy Res. 2018; 140: 199-208. doi: 10.1016/j.eplepsyres.2018.01.011.

Wang ML, et al. Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy. Pharmacol Res. 2021; 169: 105610. doi: 10.1016/j.phrs.2021.105610.

The changes in UGT1A1 are recommended to be described in detail as that of UGT1A4 in pregnancy population (figure 2).

Table 6 could be presented consistently with Table 5, which included the baseline, the estimates of PK parameters during the pregnancy.

Model credibility evaluation needs to be described in detail. Which studies were included to derive average fold error (AFE) and absolute average fold error (AAFE)? The AFE and AAFE could be stratified by trimester during pregnancy.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript describes  development and validation of PBPK models for LTG and RTG in pregnancy population using the Simcyp v.21 simulator. The results obtained may be interesting for clinicians and clinical pharmacists, however, several issues need clarification/improvements:

 1. The introduction is too long. The same information were provided in the table 1 and in the text. The  introduction should be shortened and the reason behind choosing the research topic and its significance should be clearly presented..

2. The aim of the study has not been formulated.

3. Table 1 has not been mentioned in the text.

4. “Absolute Clearance values are reported as Dose/Concentration” – it should be D/AUC (p. 4)

5. What is Michaelis-Mechen constant? (Table 3)

6. Some parameters in Table 3 have no units, e.g. Km, Vmax.

7. Equation 3 seems incomplete. No "="

8. What does GW mean in eq. 3?

9. used in equation (3) used – too many “used”

10. AFE and AFEE -  abbreviations were explained twice (p. 7 and 13)

11. Figure 6. Predcited-to-observed?

12. Figure 4 and 6 have different descriptions (dosing (fig. 4) or probably authors’ names (fig. 6)).

13. p.13, line 290 should be rather Tab.7

14. The simulations of the studied compound levels in tissues and fetus should be presented.

15. Are there any therapeutic ranges proposed for the studied drugs? This issue should be discussed in the discussion section.

16. The practical applications of the study results should be stressed, e.g. how the dosage adjustment can be performed with the newly developed models.

The quality of English is good. There are only several mistakes, mainly typos.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors well addressed the comments. I have no further questions.

Reviewer 2 Report

The Authors adequately addressed my comments. I have no further concerns.