METHODS AND FINDINGS: Published 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.
CONCLUSIONS: The 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).