Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria

Abstract

Aims: To study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria. Methods: The disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine- dihydroartemisinin coformulation Artekin®. All patients were given Artekin® orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32-35 mg base kg-1. Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17-19 samples) or sparse (2-5 samples) blood sampling schedules over 35 days and clinical/parasitological follow-up over >28 days. Piperaquine in plasma was quantified by high performance liquid chromatography. Results: All patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28-day cure rate was 97% in adults and 98% in children. A covariate-free two-compartment population model with first-order absorption and elimination gave the most robust representation of the plasma concentration-time data in both adults and children. In adults (n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/F, V55/F and f 1/2,z were 0.9 l h-1 kg-1 (0.79-1.02 l h -1 kg-1), 574 l kg-1 (371-711 l kg -1) and 23 days (19-28 days), respectively. In children (n = 47), corresponding values were 1.8 l h-1 kg-1 (1.29-2.3 l h-1 kg-1), 614 l kg-1 (332-1205 l kg -1) and 14 days (10-18 days), respectively. Conclusions: Piperaquine is a highly lipid-soluble drug with a large V55/F, long t 1/2,z and a clearance that is markedly higher in children than in adults.