College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Br J Clin Pharmacol. 2022 Aug;88(8):3674-3682. doi: 10.1111/bcp.15310. Epub 2022 Mar 25.
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.
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.
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.
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.
跨性别女性（TGW）在试验中代表性不足，且使用的性别肯定激素疗法（GAHT）可能通过显著增加肌酐清除率来改变肾功能。群体药代动力学（popPK）模型和模拟将有助于理解 TGW 在 GAHT 下与未暴露于 GAHT 的顺性别男性（CGM）相比，恩曲他滨/替诺福韦二吡呋酯（F/TDF）母体代谢物浓度的潜在差异。
使用直接观察每日 F/TDF 治疗的 1 期、开放标签临床试验的药代动力学（PK）数据进行模型构建，该试验包括 8 名 TGW 和 8 名 CGM。使用非线性混合效应建模（NONMEM 7.5.0）进行 popPK 分析。评估体重、肌酐清除率和性别等协变量。最后模型进行蒙特卡罗模拟，比较 TGWAHT 下每日一次和按需（IPERGAY 2+1+1）给药后药物暴露情况。
替诺福韦（TFV）和恩曲他滨 PK 最好由 2 室模型描述，具有吸收滞后时间的一级吸收/消除。母体模型通过一级形成和消除与其代谢物相关联。肌酐清除率是影响两种模型清除率的重要协变量。模拟表明，TGW 在 GAHT 下至少每周 2 次、2+1+1 次按需给药，才能在 CGM 初始按需给药后的第 1 周达到类似的 TFV-二磷酸盐暴露。
建立了 TGW 中 TFV、恩曲他滨和细胞内代谢物的 popPK 模型。剂量模拟表明，TGW 应至少治疗 2 周，才能达到与 CGM 相似的暴露。
