@article{d9c3a4d26c724c329eeb345e21571362,
title = "Population pharmacokinetics of tenofovir, emtricitabine and intracellular metabolites in transgender women",
abstract = "Aims: Transgender women (TGW) have been underrepresented in trials and use gender-affirming hormonal therapies (GAHT) that may alter renal function by significantly increasing creatinine clearance. Population pharmacokinetic (popPK) models and simulations would aid in understanding potential differences in emtricitabine/tenofovir disproxil fumarate (F/TDF) parent–metabolite concentrations in TGW on GAHT when compared to cisgender men (CGM) not exposed to GAHT. Methods: Pharmacokinetic (PK) data from a Phase 1, open-label clinical trial with directly observed therapy of daily F/TDF consisting of 8 TGW and 8 CGM was utilized for model building. PopPK analysis was performed using nonlinear mixed effects modelling (NONMEM 7.5.0). Covariates of body weight, creatinine clearance, and gender were evaluated. Final models were subjected to Monte Carlo simulations to compare drug exposure following once daily and on-demand (IPERGAY 2 + 1 + 1) dosing of F/TDF. Results: Tenofovir (TFV) and emtricitabine PK were best described by a 2-compartment model, first-order absorption/elimination with absorption lag time. Parent models were linked to their metabolites by first order formation and elimination. Creatinine clearance was a significant covariate influencing clearance in both models. Simulations demonstrated that at least 2, weekly 2 + 1 + 1 cycles of on-demand dosing in TGW on GAHT is necessary for TFV-diphosphate to reach similar exposure after the initial week of on-demand dosing in CGM not on GAHT. Conclusion: PopPK models of TFV, emtricitabine and intracellular metabolites in TGW were established. Dose simulations revealed that TGW should be treated for at least 2 weeks to have comparable exposures to CGM.",
keywords = "HIV, popPK model, population pharmacokinetics, pre-exposure prophylaxis, tenofovir, transgender women",
author = "Asama Tanaudommongkon and Ayyappa Chaturvedula and Hendrix, {Craig W.} and Fuchs, {Edward J.} and Eugenie Shieh and Bakshi, {Rahul P.} and Marzinke, {Mark A.}",
note = "Funding Information: M.A.M., E.J.F. and C.W.H. receive funded research support from Gilead Sciences, Merck and ViiV Healthcare. C.W.H. sits on a scientific advisory board for Merck. E.J.F. and C.W.H. are founders and officers of Prionde Biopharma. The other authors note no conflicts of interest. Funding Information: This work was supported by the and National Institutes of Health, National Institute of Allergy and Infectious Diseases under award number R01 AI145675 (Principal Investigator: Marzinke). In addition, data generated during the phase 1 study were supported, in part, by the Johns Hopkins Center for AIDS Research through a developmental research grant (P30 AI042855; Principal Investigator: Hendrix) and the Clinical Pharmacology Training Program grant (Dr. Shieh, T32 GM066691). Funding Information: We thank the study participants for their essential contributions to the clinical research that formed this basis of the described model. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins CFAR or NIH. This work was supported by the and National Institutes of Health, National Institute of Allergy and Infectious Diseases under award number R01 AI145675 (Principal Investigator: Marzinke). In addition, data generated during the phase 1 study were supported, in part, by the Johns Hopkins Center for AIDS Research through a developmental research grant (P30 AI042855; Principal Investigator: Hendrix) and the Clinical Pharmacology Training Program grant (Dr. Shieh, T32 GM066691). Publisher Copyright: {\textcopyright} 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.",
year = "2022",
month = aug,
doi = "10.1111/bcp.15310",
language = "English",
volume = "88",
pages = "3674--3682",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "8",
}