Safety and pharmacokinetics of dolutegravir dispersible tablets and oral films in term neonates exposed to HIV in South Africa (PETITE-DTG study): an open-label, randomised, phase 1/2 trial

Abstract

Background: Dolutegravir is not recommended for neonates (age 28 days or younger) due to the absence of dosing guidelines and safety information. We evaluated the multidose pharmacokinetics and safety of two paediatric dolutegravir formulations in neonates: a scored dispersible tablet and a novel oral dispersible film.

Methods: We did a phase 1/2, open-label, single-centre, two-stage, randomised trial in neonates at Tygerberg Hospital, South Africa, who were born at term (≥37 weeks gestational age, birthweights ≥2 kg) to pregnant women on dolutegravir-based antiretroviral therapy. Neonates in stage two were randomly assigned (1:1) to receive 5 mg dolutegravir either as half of a scored dispersible tablet (10 mg) or one oral dispersible film (5 mg), administered every 48 h for the first 2 weeks of life, followed by daily up to day 28 of life. Plasma pharmacokinetic samples were collected during three visits: at entry (before and 1-3 h after the first dolutegravir dose); at any time from the third dolutegravir dose but before week 4 of life (before and 1, 2, 4, 6, and 48 h after the dolutegravir dose); and during week 4 of life (before and 1-3 h after the dolutegravir dose). The primary outcomes were dolutegravir pharmacokinetic parameters of area under the concentration time curve (AUC), maximum plasma concentration (C_max), apparent clearance (CL/F), and trough concentration (C_trough) in participants who completed intensive pharmacokinetic sampling and occurrence of non-treatment-related and treatment-related adverse events of grade 3 or higher and any adverse events in participants who received at least one dose of dolutegravir. Target pharmacokinetic criteria were geometric mean C_trough higher than 0·67 μg/mL and individual C_max lower than 17·0 μg/mL. The trial is registered with ClinicalTrials.gov, NCT05590325.

Findings: Between Sept 15, 2023, and Nov 6, 2024, 41 neonates were enrolled, randomly assigned, and received dolutegravir (21 [51%] received dispersible tablets and 20 [49%] received dolutegravir films); 25 (61%) neonates were male and 16 (39%) were female. Median birthweight was 3235 g (range 2365-4330) and the first dolutegravir dose was administered at median 47 h (range 22-78) after birth. Intensive dolutegravir pharmacokinetic profiles sampled after at least three doses of dolutegravir (range 6-10 days of life) were similar between the dolutegravir dispersible tablet and the dolutegravir film and the dolutegravir geometric mean area under the concentration time curve (AUC_0-48), and CL/F were 193·2 μg x h/mL and 0·026 L/h, respectively. Both formulations attained a dolutegravir geometric mean C_trough higher than 0·67 μg/mL. All neonates had a dolutegravir C_max lower than 17·0 μg/mL at every pharmacokinetic visit. No adverse events were related to dolutegravir. Two grade 3 adverse events, the highest severity observed, occurred in one neonate with pneumonia. A total of 22 adverse events occurred in 12 (57%) of the 21 neonates receiving dolutegravir dispersible tablets and 23 adverse events occurred in 14 (70%) of the 20 neonates receiving dolutegravir films. All 39 neonates who completed follow-up were HIV negative at study exit.

Interpretation: To our knowledge, this is the first evidence providing dolutegravir dosing guidance from birth up to week 4 of life, supporting inclusion into national and international antiretroviral dosing guidelines.

Funding: Unitaid.