Abacavir Dosing in Neonates from Birth to 3 Months of Life

Background: No evidence-based dosing guidance is available for abacavir (ABC) liquid formulation use from birth. Newly available ABC pharmacokinetic (PK) data from neonates and immature infants were used to determine the optimal ABC dosing strategy (mg/kg) for infants 0-3 months and propose dosing per World Health Organization (WHO) weight-bands for neonates. Methods: Abacavir PK and safety data were pooled from three studies: (1) PACTG 321 (2) the Tygerberg Cohort and (3) IMPAACT P1106. Studies 1 and 2 were performed in neonates exposed to HIV receiving a single dose of ABC. Study 3 included predominantly low birth weight (LBW; <2500g) infants on antiretroviral therapy enrolled <3 months of life. We developed a population PK model and performed simulations to achieve ABC exposures (AUC 0-12 ) within the range 3·2-25·2 mcg.hr/mL reported in children. Findings: Forty-five infants contributed 308 ABC concentrations; 21 neonates were <15 days of life. At first PK assessment, median post-natal age was 1·0, 9·5 and 73 days, and median weight was 3·1, 3·3 and 3·8 kg for each study, respectively. ABC clearance was ~5-fold lower than adults at birth but rapid increased in early life.  Therapeutic targets were achieved with exact ABC doses of 2·0 mg/kg BID from 0-4 weeks and 4·0 mg/kg BID from 4-12 weeks. A fixed weight-band dosing strategy of 8 mg (2-3 kg), 10 mg (3-4 kg) and 12 mg (4-5 kg) ABC BID achieved target exposures throughout the first 4 weeks of life without dose adjustment for weight changes were necessary. No Grade 3 or more adverse event was ABC related.   Interpretation: We propose the first evidence-based ABC dosing strategy from birth using both exact and weight-band dosing for the liquid formulation. Integration of these new ABC dosing recommendations into National and International guidelines will provide an additional antiretroviral option from birth that is easily implementable. Trial Registration: Clinical trial.gov Identifier: NCT02383849 (P1106), NC0864 (PACTG 321) Funding: For PACTG321 and IMPAACT P1106, overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Tygerberg Cohort study was supported by the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) - Growing the Leaders of Tomorrow Fellowship Programme. Declaration of Interest: AB, EVC, AV, MFC, RM, HR and MM received funding from the IMPAACT Network. MM received funding from Gilead Sciences, Merck & Co, and ViiV Healthcare. HR received funding from Abbvie. INCOMPLETE Ethical Approval: All studies were approved by the institutional review board responsible for study oversight. Written informed consent was obtained from all infants’ mothers/legal caregivers prior to entry.