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)).
Conclusions:
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.
