Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)

Abstract

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Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)

Hardik Chandasana¹, Sven van Dijkman¹, Rashmi Mehta¹, Mark Bush², Helena Rabie³, Patricia Flynn⁴, Tim Cressey⁵, Edward Acosta⁶, Kristina Brooks⁷ and IMPAACT 2019 Protocol Team⁸

¹GSK; ²ViiV Healthcare; ³University of Stellenbosch; ⁴St. Jude Children's Research Hospital; ⁵Chiang Mai University; ⁶University of Alabama at Birmingham; ⁷University of Colorado Anschutz Medical Campus; ⁸The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network

Background: Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG) and lamivudine (3TC) have been approved in the United States 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 paediatric 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, multicentre, 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 paediatric PopPK models for ABC (two-compartment), DTG (one-compartment) and 3TC (one-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 predefined 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 AUC_0–24 ranged from 14.89 to 18.50 μg*h/mL for both formulations. Similarly, predicted GM AUC_0–24 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 and comparable to the previously observed PK with adults and paediatric participants with individual drugs.

Conclusions: This model-based approach leveraged existing paediatric 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.