Sonoko Kawakatsu1, Yanan Zheng1, Anita Wen1, Vinicius Adriano Vieira1, Xiaoning Wang1
1Gilead Sciences, Inc.
Objectives: Tenofovir alafenamide (TAF) is a second generation oral prodrug of tenofovir (TFV), a nucleotide analog that inhibits HIV type 1 (HIV-1) reverse transcription. The objectives of the current analysis were to develop a population pharmacokinetics (PK) model of TAF and TFV in children and adolescents with HIV-1, and to evaluate the effects of intrinsic and extrinsic factors on TAF and TFV PK. The final models were used to simulate steady-state exposures of TAF and TFV in children and adolescents with HIV-1 = 2 years of age weighing = 14 kg treated with various TAF-containing combination regimens. Methods: Data were pooled from five Phase 2/3 studies in children and adolescents 2 to <18 years of age with HIV-1. The population PK analysis was conducted in NONMEM v7.5 [1]. Population and individual model parameters were estimated using the stochastic approximation expectation maximization method followed by Monte Carlo importance sampling. A full covariate modeling approach was implemented to evaluate covariate effects. Monte Carlo simulations were conducted using the final model parameters. Steady-state exposure metrics were evaluated over 1000 simulation replicates in a virtual population sampled from the NHANES database [2], stratified by sex and weight groups of interest (i.e., 14-<25 kg, 25-<35 kg, = 35 kg). Simulated TAF doses were 6 mg once daily (QD) (14-<25 kg) or 10 mg QD (= 25 kg) for elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF, and 15 mg QD (14-<25 kg) or 25 mg QD (= 25 kg) for all other regimens. Results: The TAF PK analysis dataset included 2507 PK observations from 382 pediatric participants. TAF PK was characterized by a one-compartment model with lag-time, sequential zero-order release, first-order absorption, and first-order elimination. For a typical 38 kg, treatment-experienced and virologically suppressed individual receiving E/C/F/TAF, the parameter estimates (95% CI) for apparent clearance and central volume (V/F) were 30.8 L/h (27.2, 34.9) and 28.0 L (22.9, 34.1), respectively. The effects of body weight were included using allometric scaling with fixed coefficients (0.75 for clearances, 1 for volumes). TAF exposure decreased with increasing body weight for weight band-based dosing. Compared to a reference subject receiving bictegravir (B)/F/TAF at the same TAF dose, combination treatments of E/C/F/TAF and boosted atazanavir (ATV) + F/TAF were associated with increased TAF exposures, while other combination treatments (lopinavir/ritonavir (LPV/r) + F/TAF, boosted darunavir (DRV) + F/TAF, unboosted F/TAF + other) had small or no effect on TAF exposures. The TFV PK analysis dataset included 3904 observations from 395 pediatric participants. TFV PK was characterized by a two-compartment model with input from the TAF central compartment and first-order elimination. Individual empirical Bayes estimates from the TAF final model were used to generate inputs for this sequential TAF-TFV model. For a typical 38 kg individual receiving E/C/F/TAF, the parameter estimates (95% CI) were 10.5 L/h (10.1, 10.9) for apparent TFV clearance, 871 L (799, 950) for apparent peripheral volume, and 3780 L (2240, 6370) for apparent intercompartmental clearance. The TFV apparent central volume was fixed to the individual estimate for the TAF V/F. Similar to the TAF model, the effects of body weight were included using fixed allometric scaling coefficients. TFV exposure decreased with increasing body weight for weight band-based dosing of TAF. Compared to the reference subject receiving B/F/TAF at the same TAF dose, combination treatments of LPV/r + F/TAF, E/C/F/TAF, boosted DRV + F/TAF, and boosted ATV + F/TAF were associated with increased TFV exposures, while unboosted F/TAF + other treatment resulted in decreased TFV exposures. Simulated TAF and TFV steady-state exposures for children = 2 years of age weighing = 14 kg with HIV-1 treated with various TAF-containing combination regimens (E/C/F/TAF, boosted ATV + F/TAF, boosted DRV + F/TAF, LPV/r + F/TAF, and B/F/TAF) were largely contained within the range observed in the adult reference. Conclusion: A sequential population PK model was developed to describe TAF and TFV PK following administration of TAF-containing regimens in adolescents and children with HIV-1. Simulations of TAF and TFV steady-state exposures following weight-band based dosing of TAF-containing regimens support the proposed TAF doses for these combination regimens.
[1] Beal S.L., Sheiner L.B., Boeckmann A.J. & Bauer R.J. (Eds). NONMEM 7.4 users guides (ICON plc, Gaithersburg, MD, 1989. –2018). [2] Health Statistics, C. N. C. for. (2017-2020). “National health and nutrition examination survey (NHANES).” Retrieved from https://www.cdc.gov/nchs/nhanes/index.htm
Reference: PAGE 33 (2025) Abstr 11495 [www.page-meeting.org/?abstract=11495]
Poster: Drug/Disease Modelling - Infection