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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

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

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Richard M Hoglund, Ishag Adam, Warunee Hanpithakpong, Michael Ashton, Niklas Lindegardh, Nicholas PJ Day, Nicholas J White, Francois Nosten, Joel Tarning
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-398) contains supplementary material, which is available to authorized users.

Competing interests

The Welcome Trust is a UK-based medical research charity and is independent of all drug companies. It has no financial links with the manufacturers of either the diagnostics tests or the drugs used in this study. The authors declare no conflict of interest.

Authors’ contributions

IA, FN, ND, and NW conceived the project. WH, NL and JT quantified the drug concentrations. RH and JT performed the pharmacokinetic analysis and wrote the first draft of the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
12936_2012_2616_MOESM1_ESM.pdf
Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Literatur
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