Pharmacokinetics of Generic Pediatric Dolutegravir Dispersible Tablet in Thai Young Children Living With HIV Weighing Below Twenty Kilograms

Abstract

Introduction: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg.

Methods: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C 24 ) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C 24 concentration.

Results: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C 24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL.

Conclusions: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

FIGURE 1.

Geometric means plasma DTG concentration-time profile of the 3 weight bands in children 3 months to <7 years old weighing 6 to <20 kg.

FIGURE 2.

Individual DTG C₂₄ (A), C_max (B) and AUC_0-24h (C) of children per each weight band. Black lines indicate geometric means of each parameter. Black dash lines indicate geometric mean adult reference value for 50 mg film-coated tablet once daily. Gray line indicates EC₉₀; the effective concentration at which 90% of maximal viral inhibition is achieved in a 10-day monotherapy study.