Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis

Abstract

BackgroundArtemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.Methods and FindingsPublished pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration–time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers’ currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3–44.3) ng/ml in small children compared to 38.1 (25.8–56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%–32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413–0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers’ recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals.ConclusionsThe derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015).

Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers

“…The 95% CI is calculated as the 2.5th to 97.5th percentile of bootstrap estimates piperaquine (below 35%). The overall pharmacokinetic parameter estimates were in agreement with previous studies in healthy volunteers and patients with P. falciparum malaria [8,23,48,50,51].…”

“…Piperaquine was described by a three-compartment disposition model, which is in agreement with recently published studies [8,[47][48][49][50]. The variable absorption characteristics of piperaquine were best described with two transit absorption compartments, compared with three or five in previous studies [8,48].…”

“…Modelling performed here demonstrated moderate variability in the absorption characteristics of piperaquine (below 35%). The overall pharmacokinetic parameter estimates were in agreement with previous studies in healthy volunteers and patients with P. falciparum malaria .…”

Combining antimalarial drugs and vaccine for malaria elimination campaigns: a randomized safety and immunogenicity trial of RTS,S/AS01 administered with dihydroartemisinin, piperaquine, and primaquine in healthy Thai adult volunteers

“…The most likely explanation is the absence of fat-containing foods with the drug administration. 21 In the reference study on which the model was built a light meal was administered at the time of antimalarial dosing, while food intake was not monitored in the present study. 20 Intake of a high-fat meal has been seen to enhance the absorption of piperaquine while smaller amounts of fat have been shown not to have an effect.…”

“…22,23 The observed piperaquine levels were well above the threshold required to kill Plasmodium species in earlier studies, and the observed piperaquine concentrations are similar to what is seen in patients during acute treatment of uncomplicated malaria. 21 Nearly all participants reported one or more adverse events. Some participants reported 14 and more AEs suggesting a highly variable threshold for reporting AEs is in this population.…”