Sonoko Kawakatsu 1, Curtis Johnston 1, Jing Niu 1, Anita Wen 1, Vinicius Vieira 1, Xiaoning Wang 1
1 Gilead Sciences, Inc. (Foster City, USA)
Introduction/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 ≥ 1 month of age with HIV-1, and to evaluate the effects of intrinsic and extrinsic factors on TAF and TFV PK.
Methods: A previously developed model [1] in children and adolescents ≥ 2 years of age and ≥ 14 kg was used as a starting point and updated with additional data in children ≥ 1 month of age and ≥ 3 kg. Data were pooled from a total of five Phase 2/3 studies in children and adolescents with HIV-1. The population PK analysis was conducted in NONMEM v7.5 [2]. 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 of clinical interest.
Results: The TAF PK analysis dataset included 2944 PK observations from 427 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 35 kg, treatment-experienced and virologically suppressed individual receiving bictegravir (B)/emtricitabine (F)/TAF, the parameter estimates (95% CI) for apparent clearance and central volume (V/F) were 76.7 L/h (69.4, 84.8) and 11.7 L (6.98, 19.7), respectively. The effects of time-varying body weight were included using allometric scaling with fixed coefficients (0.75 for clearances, 1 for volumes). After accounting for body weight, no additional trends in PK parameters by age were observed. TAF clearance increased with increasing body weight. Compared to a reference subject receiving B/F/TAF at the same TAF dose, combination treatments of elvitegravir (E)/cobicistat (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 , unboosted F/TAF + other) had small or no effect on TAF exposures.
The TFV PK analysis dataset included 4422 observations from 430 pediatric participants. TFV PK was characterized by a two-compartment model with first order 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. Typical parameter values based on individual covariates were used for participants with no TAF PK. For a typical 35 kg individual receiving B/F/TAF tablet, the parameter estimates (95% CI) were 37.1 L/h (35.3, 39.0) for apparent TFV clearance, 1580 L (1410, 1770) for apparent peripheral volume, and 3480 L/h (2650, 4570) for apparent intercompartmental clearance. The TFV apparent central volume was fixed to the individual estimate for the TAF V/F, and the conversion fraction was fixed to 1 with interindividual variability estimated. Similar to the TAF model, the effects of time-varying body weight were included using fixed allometric scaling coefficients. A sigmoidal Emax function based on postmenstrual age was estimated on apparent TFV clearance to reflect the maturation and development of organ functions in pediatric participants. The model estimated half-maximal maturity of clearance at a postmenstrual age of 41 weeks. The Hill coefficient was fixed to 3.4, based on a published model for renal function maturation [3]. TFV clearance increased with increasing body weight. The tablet for oral suspension was associated with 27% lower steady-state AUC compared to the reference tablet formulation. 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.
Conclusions: A sequential population PK model with a maturation function on TFV clearance was adequate to describe TAF and TFV PK following administration of TAF-containing regimens in adolescents and children with HIV-1. The current model can be used to support dosing recommendations in children ≥ 1 month of age and ≥ 3 kg.
References:
[1] Kawakatsu S, Zheng Y, Wen A, Vieira VA, Wang X. Population Pharmacokinetic Analysis of Tenofovir Alafenamide (TAF) and Tenofovir (TFV) in Adolescents and Children with HIV-1. PAGE 2025.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds). NONMEM 7.4 users guides (ICON plc, Gaithersburg, MD, 1989. –2018).
[3] Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76. doi: 10.1007/s00467-008-0997-5. Epub 2008 Oct 10. PMID: 18846389.
Reference: PAGE 34 (2026) Abstr 12249 [www.page-meeting.org/?abstract=12249]
Poster: Drug/Disease Modelling - Paediatrics