Xiaoning (Shelly) Wang1, Sonoko Kawakatsu1, Anita Wen1, Vinicius A. Vieira1, Yanan Zheng1
1Gilead Sciences
Objectives: Emtricitabine (FTC) is a nucleoside reverse transcriptase inhibitor (NRTI) that has demonstrated potent and selective inhibition of human immunodeficiency virus (HIV). It is an NRTI that is usually co-formulated with tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF). In adults with HIV, FTC is administered as a 200-mg once daily (QD) dose concurrently with other antiretroviral (ARV) drugs.
The objectives of the current analysis were to develop a population pharmacokinetics (PK) model of FTC in adolescents and children with HIV-1, and to evaluate the effects of intrinsic and extrinsic factors on FTC PK. The final models were used to simulate steady-state exposures of FTC in children with HIV-1 ≥2 years of age weighing ≥14 kg treated with various FTC-containing combination regimens.
Methods: Data were pooled from six Phase 2/3 studies in children 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 population PK 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, 200 subjects per weight group). Simulated FTC dose was 120 mg once daily (QD) (14-<25 kg) or 200 mg QD (≥25 kg).
Results: The analysis dataset included a total of 4597 PK observations from 437 pediatric participants. FTC PK was characterized by a two-compartment model with five transit compartments followed by first-order absorption and first-order elimination. For a typical 40-kg individual receiving elvitegravir (E)/cobicistat (C)/FTC/TAF (F/TAF), the apparent clearance (CL/F) (95% CI) and central volume (V/F) were estimated at 12.1 L /h (11.6, 12.7) and 64.4 L (61.4, 67.5), respectively. The mean transit time (MTT) was estimated at 0.696 h (0.586, 0.826).
The effects of body weight were included using allometric scaling with fixed coefficients (0.75 for clearance, 1 for volume). FTC exposure decreased with increasing body weight for weight band-based dosing. There was a trend of higher FTC exposure from the treatment of boosted atazanavir (ATV)+F/TAF or boosted darunavir (DRV)+F/TAF, relative to the reference subject receiving bictegravir(B)/F/TAF. Exposure from the treatment of E/C/F/TAF was also slightly higher than the reference. Exposure from lopinavir/ritonavir (LPV/r)+F/TAF was slightly lower than B/F/TAF.
Using the adult exposures from the E/C/F/TAF, B/F/TAF and E/C/F/TDF phase 2/3 program as the reference, simulated FTC steady-state exposures under weight-band based dosing for children ≥2 years of age weighing ≥14 kg with HIV-1 treated with various FTC-containing combination regimens were largely contained within the range observed in the adult reference.
Conclusion: A population PK model was developed to adequately describe FTC concentrations over time in adolescents and children with HIV-1. Simulations of FTC steady-state exposures following weight-band based dosing regimens support FTC 200 mg QD for patients weighing ≥25 kg, and 120 mg QD for patients weighing ≥14 to <25 kg.
[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 11742 [www.page-meeting.org/?abstract=11742]
Poster: Drug/Disease Modelling - Paediatrics