Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand

Abstract

The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three-and four-dose regimens. Children had a lower body weightnormalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC day 0-63 ]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC day 3-20 ) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

“…Most previous studies have used a two-compartment model (28,31,44). One study in healthy adults found that, although a three-compartment model represented the postadministration profile better, there were insufficient data to support its use over a two-compartment model (38).…”

“…The current manufacturer's recommendation is for Artequick to be given as a 2-day regimen, which contrasts with the 3 days recommended for all ACTs by the WHO (48). Although the tolerability, safety, efficacy, and pharmacokinetics (PK) properties of DHA-PQ tetraphosphate have been widely investigated in children and adults (27,28,36,44,49), there are limited data relating to the efficacy and tolerability of ART-PQ base (37,46) and no studies of the pharmacokinetics of this novel combination in malaria-infected patients. Concerns have been raised regarding possible underdosing in children for a number of antimalarial drugs (8,33), including PQ (27,36,49).…”

“…Concerns have been raised regarding possible underdosing in children for a number of antimalarial drugs (8,33), including PQ (27,36,49). Although children have been included in studies of PQ pharmacokinetics (28,44), only one pharmacokinetic study of ART has specifically enrolled pediatric patients (40).…”

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

“…In order to prevent drug resistance and early parasite recrudescence associated with the short-acting artemisinin drugs, ACT partner drugs should be long-acting schizonticides with half-lives (t 1/2 s) exceeding 4 days, or two asexual parasite life cycles (10,21). Recent pharmacokinetic studies have demonstrated that PQ has biphasic elimination and a long terminal t 1/2 of 12 to 28 days in humans (10,15,31,32).…”

“…In order to prevent drug resistance and early parasite recrudescence associated with the short-acting artemisinin drugs, ACT partner drugs should be long-acting schizonticides with half-lives (t 1/2 s) exceeding 4 days, or two asexual parasite life cycles (10,21). Recent pharmacokinetic studies have demonstrated that PQ has biphasic elimination and a long terminal t 1/2 of 12 to 28 days in humans (10,15,31,32).Several clinical trials of the PQ-dihydroartemisinin combination have shown that it has a high degree of efficacy and good tolerability for the treatment of Plasmodium falciparum infections (1,2,5,7,11,12,17). While this combination is now considered the first-line antimalarial treatment in some Southeast Asian countries, the long t 1/2 of PQ raises concerns about adverse effects and drug resistance (6,10,20,22).…”