CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

943

High Drug Exposures in Neonates Using ABC/3TC Dispersible Tablets During the First Week of Life Navarat Panjasawatwong 1 , Adrie Bekker 2 , Helena Rabie 2 , Nicolas Salvadori 3 , Samantha du Toit 2 , Kanchana Than-in-at 3 , Maria Groenewald 2 , Edmund Capparelli 4 , Ratchada Cressey 3 , Marc Lallemant 3 , Mark F. Cotton 2 , Tim R. Cressey 5 , for the PETITE Study Team 1 Payap University, Chiang Mai, Thailand, 2 Stellenbosh University, Cape Town, South Africa, 3 Chiang Mai University, Chiang Mai, Thailand, 4 University of California San Diego, San Diego, CA, USA, 5 AMS PHPT Research Collaboration, Chiang Mai University, Chiang Mai, Thailand Background: Pediatric fixed dose combination (FDC) formulations are preferred for infants and young children but rapid maturation of metabolic and elimination pathways complicate their use in neonates. We previously reported the pharmacokinetics (PK) and safety of abacavir/lamivudine (ABC/3TC) FDC dispersible tablet in neonates but no PK data were available prior to 6 days of life. Our objective was to develop population PK models to estimate ABC/3TC exposures in neonates using ABC/3TC dispersible tablets from birth. Methods: The 'PETITE' study was a phase I/II, open-label, single arm, two-stage pharmacokinetic and safety trial. HIV-exposed neonates received 30/15 mg of ABC/3TC (¼ dispersible tablet) once daily and 80/20 mg of LPV/r (2 sachets) twice daily through 28 days of life. Each neonate had intensive PK sampling on two occasions between 6 and 24 days of life. Safety visits were performed 1-2 week(s) after each PK visit. PK models of ABC and 3TC were developed using nonlinear mixed-effects modeling. Monte Carlo simulations (n=5,600 virtual neonates) were performed to predict ABC and 3TC exposures from birth through 28 days of life. Geometric mean (GM) ABC and 3TC target exposures (AUC0-24) reported in children were 6.3 to 50.4 and 6.3 to 26.5 mg.hr/L for ABC and 3TC, respectively. Results: 16 term neonates (8 females) with a median birth weight of 3,140 g were included. One compartment PK models with first-order absorption and elimination best described both ABC and 3TC plasma concentrations, incorporating body weight and postnatal age on clearance as surrogates of hepatic and renal maturation. Simulations predicted that maximum ABC and 3TC exposures occurred at 2 days of life. The predicted GM ABC AUC0-24 decreased by 28% between 2 and 7 days of life and remained above the target during the first week of life (Figure 1(a)). The GM 3TC AUC0-24 decreased by 26% between 2 and 4 days of life and remained above the target during the first 4 days of life (Figure 1(b)). Conclusion: Administrating 30/15 mg of ABC/3TC (¼ dispersible tablet) once daily to neonates from birth leads to plasma exposures during the first week of life above those observed in young children. While no safety issues were reported in the PETITE study, continued safety surveillance of the ABC/3TC dispersible tablets in neonates is warranted, particularly when stared in the first week of life.

942

Lamivudine (3TC) Dosing for Preterm Neonates Exposed to HIV Adrie Bekker 1 , Edmund Capparelli 2 , Mark Mirochnick 3 , Diana F. Clarke 4 , Mark F. Cotton 1 , Roger Shapiro 5 , Katie McCarthy 6 , Jack Moye 7 , Avy Violari 8 , Kulkanya Chokephaibulkit 9 , Elaine J. Abrams 10 , Martina Penazzato 11 , Theodore Ruel 12 , Tim R. Cressey 13 1 Stellenbosh University, Cape Town, South Africa, 2 University of California San Diego, San Diego, CA, USA, 3 Boston University, Boston, MA, USA, 4 Boston Medical Center, Boston, MA, USA, 5 Harvard TH Chan School of Public Health, Boston, MA, USA, 6 FHI 360 , Durham, NC, USA, 7 National Institute of Child Health and Human Development, Bethesda, MD, USA, 8 University of the Witwatersrand, Johannesburg, South Africa, 9 Mahidol University, Bangkok, Thailand, 10 Columbia University, New York, NY, USA, 11 World Health Organization, Geneva, Switzerland, 12 University of California San Francisco, San Francisco, CA, USA, 13 Chiang Mai University, Chiang Mai, Thailand Background: Current oral lamivudine (3TC) dosing guidance for preterm neonates exposed to HIV is based on limited evidence and no pharmacokinetic (PK) studies in neonates <36 weeks gestational age (GA). As 3TC is one of only three antiretrovirals available for preterm neonates, our aim was to develop a pragmatic 3TC twice daily preterm dosing strategy stratified by GA bands: ≥27 to <30 weeks; and ≥30 to <36 weeks Methods: 3TC plasma concentration data were pooled from 8 neonatal and infant PK studies receiving 3TC liquid formulation (10 mg/mL); 3 for HIV prevention (PACTG 353, 358, and 386), and 5 for HIV treatment (PACTG 300, 356, IMPAACT P1069, P1106, and the Early Infant HIV Treatment in Botswana study). A population PK model was developed using non-linear mixed effects regression. Different dosing simulations were assessed in a virtual population of preterm neonates (0-6 months of life) to achieve 3TC (AUC 0-12 ) exposures ranging from 3.15 to 13.24 µg∙hr/mL. The model incorporated standard WHO weight-band 3TC dosing of 30 mg twice daily for weights ≥3 to <6 kg and ≥4 weeks of life. Results: One-hundred fifty-four infants contributed 858 3TC concentrations; 34 (22%) were born preterm. At first PK sampling, median and range postnatal age (PNA) was 6.3 (0.52-26.6) weeks, body weight 3.8 (1.9-7.8) kg, and plasma serum creatinine 0.4 (0.1-1.2) mg/dL, respectively. 3TC concentrations were best described by a 1 compartment PK model. 3TC clearance (CL/F) and volume of distribution (Vd/F) were allometrically scaled to body weight. Maturation of CL/F was described using an Emax model based on PNA, which also influenced Vd/F. Simulations included GA as a covariate on birth CL/F to account for the impact of developmental changes in renal function expected in preterm neonates. The simulations predict that the optimal 3TC dosing regimen for preterm neonates for GA ≥27 to <30 weeks is 2 mg/kg twice daily from birth, and for GA ≥30 to <36 weeks is 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily. Dosing is adjusted to 30 mg twice daily per WHO weight-band dosing once infants reach ≥ 3kg and aged ≥4 weeks (Figure 1). Conclusion: This analysis provides the first pragmatic and evidence based 3TC dosing for preterm neonates where immature renal function undergoes rapid maturation. This proposed preterm 3TC dosing guidance has been endorsed by the WHO-Pediatric Antiretroviral Working Group but should be clinically validated to provide reassurance of model predictions.

Poster Abstracts

CROI 2024 298