Background:
Dolutegravir dispersible tablets (DTG-DT) are approved for infants ≥3 kg and aged >4 weeks but their suitability for neonates remains unknown. We evaluated the pharmacokinetics (PK) and safety of pediatric DTG-DT in neonates born to women on DTG-based therapy.
Methods:
PETITE-DTG is an ongoing phase I/II, open-label, single center, two-stage trial in South Africa evaluating the PK and safety of DTG-DT (10 mg, scored) in term neonates (birth weights ≥2kg). Stage 1 was designed to assess single doses of DTG on top of standard ARV prophylaxis to inform a multi-dose strategy in Stage 2. In Stage 1, a single 5 mg DTG-DT dose was administered to 8 neonates between ≥14 & <28 days of life (Cohort 1A) followed by intensive PK and safety assessments. After no safety signal was observed, 8 additional neonates received a single 5 mg DTG-DT dose at <14 days of life (Cohort 1B) followed by identical PK and safety assessments. A population PK model was developed using Stage 1 data, and different dosing scenarios were simulated to select the optimal 5 mg DTG multi-dose strategy through 28 days of life [target DTG criteria: geometric mean (GM) Ctau >0.67 µg/mL and individual Cmax <17.0 µg/mL]
Results:
16 neonates, 8 per Cohort, completed Stage 1. Median (range) birth weight was 3.1 (2.6-4.2) kg and PK sampling performed between 3 to 22 days of life (Figure a). Single dose DTG Cmax ranged from 2.0-6.6 µg/mL. No grade ≥3 adverse events (AEs) were reported, and no AEs were related to DTG. One neonate required hospitalization for a skin rash (grade 2). A one-compartment PK model described DTG plasma concentrations, with clearance (CL/F) influenced by weight and postnatal age. DTG CL/F rapidly increased after birth with ~6-fold change between day 1 and 14 of life. Simulations predicted >10% of neonates had a Cmax>17.0 µg/mL with 5 mg DTG-DT once daily (q24) during the first 2 weeks of life. Administration of 5 mg DTG-DT every 48 hrs (q48) from Day 1 to 14 of life, followed by 5 mg DTG q24 though day 28 day would be an optimal dosing strategy (Figure b) with the predicted Ctau between 0.86-4.35 µg/mL and 98% of neonates with a Cmax <17.0 µg/mL.
Conclusions:
Single doses of 5 mg DTG-DT were safe in neonates. Due to slow DTG CL/F in early life, 5 mg DTG q24 was not optimal from birth. In Stage 2, the safety and PK of 5 mg DTG q48 for the first 2 weeks of life, followed by q24 through 28 days of life, will be assessed. Both the DTG-DT and the recently approved 5 mg DTG oral dispersible film will be investigated.
