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

Richard M Hoglund1, Ishag Adam2, Warunee Hanpithakpong3, Michael Ashton1, Niklas Lindegardh34, Nicholas PJ Day34, Nicholas J White34, Francois Nosten345 and Joel Tarning34*

Author Affiliations

1 Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden

2 Faculty of Medicine, University of Khartoum, Khartoum, Sudan

3 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 60th Anniversary Chalermprakiat Building, 420/6 Rajvithi Road, Bangkok, 10400, Thailand

4 Centre for Tropical Medicine, Department of Clinical Medicine, Churchill Hospital, Oxford, UK

5 Shoklo Malaria Research Unit, Mae Sot, Thailand

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Malaria Journal 2012, 11:398  doi:10.1186/1475-2875-11-398

Published: 29 November 2012

Abstract

Background

Pregnancy 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.

Method

Symptomatic 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.

Results

A 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.

Conclusions

The 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.

Keywords:
Malaria; Piperaquine; Pregnancy; Population pharmacokinetics; Nonlinear mixed-effects modelling