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

Journal article

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.

Authors: Hoglund, R; Adam, I; Hanpithakpong, W; Ashton, M; Lindegardh, N

• Publication status: Published
• Journal: Malaria journal
• Volume: 11
• Issue: 1
• Pages: 398
• Publication date: 2012-01-01
• DOI: 10.1186/1475-2875-11-398
• EISSN: 1475-2875
• ISSN: 1475-2875
• Language: English
• Keywords: Drug Combinations; Models, Biological; Malaria, Falciparum; Nonlinear Dynamics; Biological Availability; Sudan; Adolescent; Quinolines; Young Adult; Metabolic Clearance Rate; Pregnancy; Artemisinins; Humans; Adult; Pregnancy Complications, Parasitic; Female; Antimalarials