Background
Dolutegravir (DTG) is approved for treatment of HIV-1 in adults and pediatric patients ≥4 weeks and ≥3 kg. We previously reported the pharmacokinetics (PK) and safety of two single doses of DTG (0.5 mg/kg) given with standard of care antiretrovirals in the first 13 days of life. Here, we describe preliminary PK and safety of 4-6 weeks DTG dosing using a 5-mg dispersible tablet (DT) formulation in neonates exposed to HIV-1.
Methods
IMPAACT 2023 is a PK, safety, and tolerability study of DTG in infants during the first 4-6 weeks of life. In this cohort, DTG 5 mg DT was dosed every other day until day 13 of life, followed by once daily dosing. Intensive PK sampling was performed at 7 days and 4 weeks after DTG initiation. Adverse events (AEs) were graded using the DAIDS grading table. DTG exposures were evaluated according to protocol-defined target geometric mean (GM) exposures: Ctrough > 0.697 µg/mL, AUC0-tau > 37 µg*h/mL, and Cmax <18.35 µg/mL. Tolerability information was collected using a questionnaire.
Results
Data were available from 8 full-term infants with maternal DTG use (DTG-exposed) and 7 DTG-naïve infants with birthweights between 2.3 – 3.6 kg and postnatal age 0 – 5 days at time of DTG initiation. Participants were enrolled from South Africa (n=8), USA (n=4), and Thailand (n=3). No clinically meaningful differences were observed in DTG exposures between DTG–exposed and DTG-naïve infants and PK results for each group were combined. PK results are displayed in Figure 1. At 7 days post-initial dose, GM (range) Ctrough, AUC0-tau, and Cmax were 1.0 µg/mL (0.05 – 4.1), 121.1 µg*h/mL (42.0 – 321.9), and 4.9 µg/mL (2.1 – 9.1), respectively. A total of 5 of 15 participants had trough concentrations below the target at 7 days post-initial dose. At week 4, GM (range) Ctrough, AUC0-tau, and Cmax were 2.3 µg/mL (0.1 – 5.1), 98.2 µg*h/mL (24.0 – 159.2), and 5.4 µg/mL (1.6 – 9.1), respectively. No neonates experienced ≥ grade 3 AEs related to study drug.
Conclusions
Use of DTG 5-mg DT (every other day for two weeks until day 14 of life, followed by once daily dosing) for 4-6 weeks was well-tolerated with no unexpected AEs in neonates exposed to HIV-1. DTG exposures met GM protocol-defined targets; however, there was considerable variability in exposures. Continued evaluation of this DTG dosing regimen including potential sources of PK variability is ongoing in IMPAACT 2023.