Single Doses of Pediatric Dolutegravir Dispersible Tablets in Neonates Support Multidosing: PETITE-Dolutegravir Study

Abstract

Background: Dolutegravir dispersible tablets (DTG-DTs) are approved for infants 4 weeks or older and ≥3 kg but their suitability for neonates remains unknown. Methods: PETITE-DTG is a phase I/II, open-label, single-center, 2-stage trial in South Africa to evaluate the pharmacokinetics (PK) and safety of DTG in term neonates of pregnant individuals receiving DTG-based therapy. In stage 1, neonates on standard antiretroviral prophylaxis received a single dose of 5 mg DTG-DT between ≥14 and <28 days of life (cohort 1A) or <14 days of life (cohort 1B), followed by PK and safety assessments. A population PK model was developed and multidose scenarios were simulated (DTG targets: geometric mean Ctau > 0.67 μg/mL and Cmax < 17.0 μg/mL). Results: Sixteen neonates, 8 per cohort, completed stage 1. The median (range) birth weight was 3.1 (2.6–4.2) kg, and PK sampling was performed between 3 and 22 days of life. No grade 3 or higher adverse events were observed. DTG clearance was influenced by body weight and postnatal age. Simulations predicted that >10% of neonates would have a Cmax > 17.0 μg/mL with DTG once daily (q24) during the first 2 weeks of life. The administration of DTG every 48 hours (q48) from day 1–14 of life, followed by DTG every 24 hours through day 28, predicted a geometric mean Ctau between 0.86 and 4.35 μg/mL; 98% with a Cmax <17.0 μg/mL. Conclusions: Owing to the slow postnatal DTG clearance after birth, a multidose strategy of 5 mg DTG-DT q48 for the first 2 weeks of life, followed by q24 through 28 days, was selected for assessment in stage 2.