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

Abstract

Background

Artemisinin-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 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).

Abstract

Joel Tarning and colleagues combine individual participant data from clinical trials to develop a pharmacokinetic model and derive an optimized dose regimen for malaria treatment in children.

Author Summary

Why Was This Study Done?

• Despite expansion of malaria prevention and treatment in the last decade, malaria still kills around 1,200 people each day, mostly children below the age of five.

• Reduced drug exposure to one of the commonly used antimalarial drug combinations, dihydroartemisinin-piperaquine, has been reported in small children.

• It is crucial to develop an optimised dose regimen that achieves similar drug exposure in all patient groups, in order to give all patients an equal chance of cure.

What Did the Researchers Do and Find?

• Drug concentration–time data (8,776 piperaquine concentration measurements) from 728 individuals in 11 separate clinical trials were collated and pooled for an individual participant data meta-analysis.

• A pharmacokinetic model was developed to describe the pharmacological properties of piperaquine, the expected variability between patients, and the influence of biologically important covariates.

• Small children had a substantially lower piperaquine exposure after recommended dosing regimens.

• The developed pharmacokinetic model was used to derive a new optimised dose regimen.

What Do These Findings Mean?

• The proposed improved dose regimen of dihydroartemisinin-piperaquine is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria.

• An optimised dose regimen should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development.