Background:
Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥6 kg (Dispersible tablet (DT) and Tablets). This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using DT and Tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study.
Methods:
IMPAACT 2019 was a Phase I/II, multi-center, open-label study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC (Tablets and DT) in children with HIV-1 aged <12 years and weighing ≥6 to <40 kg. Intensive and sparse PK samples were collected through 48 weeks (N=55 participants with 590 ABC, 598 DTG, and 597 3TC observations). Existing drug specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 plasma drug concentrations data without re-estimation (external validation) of PopPK parameters. Exposures were then simulated across weight bands for each drug and compared with pre-defined exposure target ranges.
Results:
Goodness-of-fit and visual predictive check plots demonstrated good agreement between observed concentrations for ABC, DTG, and 3TC from IMPAACT 2019 and the respective PopPK models. The post-hoc PK parameter estimates were comparable to the NCA PK parameter estimates from IMPAACT 2019. Thus, new PopPK models to specifically describe the IMPAACT 2019 data were not necessary. Simulated geometric mean (GM) C24h DTG exposures were consistent across the weight bands (0.74 – 0.95 μg/mL) for both formulations. The predicted ABC GM AUC0-24 ranged from 14.89 to 18.50 μg*h/mL for both formulations. Similarly, predicted GM AUC0-24 ranges for 3TC were consistent across the weight bands (10.50 – 13.20 μg*h/mL). The predicted GM exposures were within the pre-defined GM target range set for each drug (Table 1) and comparable to the previously observed PK with adults and pediatric participants with individual drugs.
Conclusions:
This model-based approach leveraged existing pediatric data and models to confirm FDC ABC/DTG/3TC dosing for DT and Tablet using PK data collected in IMPAACT 2019. This analysis supports ABC/DTG/3TC FDC dosing in children weighing ≥6 kg.
