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Meta-Analysis
. 2017 Jan 10;14(1):e1002212.
doi: 10.1371/journal.pmed.1002212. eCollection 2017 Jan.

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

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Free PMC article
Meta-Analysis

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

Richard M Hoglund et al. PLoS Med. .
Free PMC article

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).

Conflict of interest statement

KIB and NJW are members of the WHO Technical Expert Group (TEG) on Malaria Chemotherapy. KIB is also a member of the WHO TEG on Drug Resistance and Containment. KIB, NJW, JT and SP are members of the WHO Malaria Chemotherapy sub-group on dosage recommendations. None of the authors declare any other conflict of interest.

Figures

Fig 1
Fig 1. Flowchart of the literature search.
Fig 2
Fig 2. A graphical overview of the final piperaquine population pharmacokinetic model.
kTR is the absorption transit rate constant. CL is the elimination clearance. VC is the volume of distribution of the central compartment. VP1 and VP2 are the volumes of distribution of the first and second peripheral compartments, respectively. Q1 and Q2 are the inter-compartment clearances for the first and second peripheral compartments, respectively. F is the relative oral bioavailability.
Fig 3
Fig 3. Basic goodness-of-fit plots for the final piperaquine model.
Observed plasma piperaquine concentrations (from 11 clinical studies) plotted against population predicted concentrations (A) and against individual predicted concentrations (B). Conditional weighted residuals plotted against population prediction (C) and time (D). The solid line is the identity line, and the dashed line is the locally weighted least squares regression line.
Fig 4
Fig 4. Prediction-corrected visual predictive check of the final population pharmacokinetic model of piperaquine.
Based on 2,000 stochastic simulations. The insert shows the first 25 h after dosing. Open circles represent the observations, and solid lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded areas represent the 95% confidence intervals around the simulated 5th, 50th, and 95th percentiles.
Fig 5
Fig 5. Stochastic simulations of dose regimens.
Maximum plasma piperaquine concentration (A–C) and day 7 plasma piperaquine concentration (D–F) after Sigma-Tau’s recommended dosing (left panels), Beijing Holley-Cotec’s recommended dosing (middle panels), and the revised dose regimen (right panels). Circles represent the median values, and vertical lines represent the 25th to 75th percentiles of simulated concentrations. The dashed line indicates the previously defined venous plasma piperaquine day 7 concentration threshold value for therapeutic success of 30 ng/ml [35].

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