R-praziquantel integrated population pharmacokinetics in preschool- and school-aged African children infected with Schistosoma mansoni and S. haematobium and Lao adults infected with Opisthorchis viverrini

Abstract

Racemic praziquantel (PZQ) is the standard treatment for schistosomiasis and liver fluke infections (opisthorchiasis and clonorchiasis). The development of an optimal pediatric formulation and dose selection would benefit from a population pharmacokinetic (popPK) model. A popPK model was developed for R-PZQ, the active enantiomer of PZQ, in 664 subjects, 493 African children (2-15years) infected with Schistosoma mansoni and S.haematobium, and 171Lao adults (15-78years) infected with Opisthorchis viverrini. Racemate tablets were administered as single doses of 20, 40 and 60mg/kg in children and 30, 40 and 50mg/kg in 129 adults, and as 3 × 25mg/kg apart in 42 adults. Samples collected by the dried-blood-spot technique were assayed by LC-MS/MS. A two-compartment disposition model, with allometric scaling and dual first-order and transit absorption, was developed using Phoenix™ software. Inversely parallel functions of age described the apparent oral bioavailability (BA) and clearance maturation in children and ageing in adults. BA decreased slightly in children with dose increase, and by 35% in adults with multiple dosing. Crushing tablets for preschool-aged children increased the first-order absorption rate by 64%. The mean transit absorption time was 70% higher in children. A popPK model for R-PZQ integrated African children over 2years of age with schistosomiasis and Lao adults with opisthorchiasis, and should be useful to support dose optimization in children. Invitro hepatic and intestinal metabolism data would help refining and validating the model in younger children as well as in target ethnic pediatric and adult groups.