Richard Höglund (1), Ishag Adam (2), Warunee Hanpithakpong (3), Michael Ashton (1), Nicholas Day (3,4), Nicholas White (3,4), Niklas Lindegardh (3,4), Francois Nosten (3,4,5), Joel Tarning (3,4)
Institution: (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) Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK; (4) Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; (5) Shoklo Malaria Research Unit, Mae Sot, Thailand
Objectives: Pregnancy has been associated with an increased risk of contracting a malaria infection and with higher risk of severe malaria. The pharmacokinetic properties of many antimalarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising antimalarial 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 P. falciparum malaria.
Methods: Patients received a standard dose regimen of the fixed oral piperaquine-dihydroartemisinin combination treatment. Dense plasma samples were collected and analysed using a previously published LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using non-linear 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 population.
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 statistical significant difference in terminal half-life between pregnant and non-pregnant women was found, but there were no differences in total drug exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women to identify pregnancy as a covariate on relevant pharmacokinetic parameters. Pregnancy was therefore evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach.
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 full covariate approach resulted in no major difference in piperaquine clearance and post-hoc estimates of piperaquine exposure were similar in the two groups. Data presented here is reassuring and do not warrant a dose adjustment on account of pregnancy in this vulnerable population.
Reference: PAGE 21 () Abstr 2583 [www.page-meeting.org/?abstract=2583]
Poster: Infection