A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in SudanReport as inadecuate

A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan - Download this document for free, or read online. Document in PDF available to download.

Malaria Journal

, 11:398

First Online: 29 November 2012Received: 20 September 2012Accepted: 22 November 2012


BackgroundPregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.

MethodSymptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS-MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power MCMP analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study.

ResultsA three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters 80% power and p=0.05. Pregnancy was, therefore, evaluated as a categorical and continuous covariate i.e. estimate gestational age in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen.

ConclusionsThe population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.

KeywordsMalaria Piperaquine Pregnancy Population pharmacokinetics Nonlinear mixed-effects modelling Electronic supplementary materialThe online version of this article doi:10.1186-1475-2875-11-398 contains supplementary material, which is available to authorized users.

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Author: Richard M Hoglund - Ishag Adam - Warunee Hanpithakpong - Michael Ashton - Niklas Lindegardh - Nicholas PJ Day - Nicholas 

Source: https://link.springer.com/

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