Abacavir drugexposures in African children under 14 kg using pediatric solid fixed dose combinations according to World Health Organization weight bands
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Abacavir drugexposures in African children under 14 kg using pediatric solid fixed dose combinations according to World Health Organization weight bands
Chupradit, Suthunya; Wamalwa, Dalton C.; Maleche-Obimbo, Elizabeth; Kekitiinwa, Adeodata R; Mwanga-Amumpaire, Juliet; Bukusi, Elizabeth A.; Nyandiko, Winstone M.; Mbuthia, Joseph K; Swanson, Alistair; Cressey, Tim R.; Punyawudho, Baralee; Musiime, Victor
Background: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and
receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population phar-
macokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands.
Methods: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets
(60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte
Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV.
ABC exposures (AUC 0–24
) of 6.4–50.4 mg h/L were used as targets.
Results: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F)
and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of
ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of
age). Exposures to ABC were within the target range for children weighing 6.0–24.9 kg, but children weighing 3–5.9 kg were pre-
dicted to be overexposed.
Conclusions: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3–5.9 kg increased the
proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical
implications and safety of the proposed alternative ABC doses.