Prof Francois Nosten (Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit,, Thailand)Principle Investigators:
Dr Rose McGready (Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit,, Thailand); Dr Joel Tarning (Mahidol, Thailand), Markus Rijken (University Medical Center Utrecht, The Netherlands)Partners:
Dr Philippe Guerin (University of Oxford, UK), Dr Philippe Brasseur (IRD, France), Prof Karen Barnes (University of Cape Town, South Africa), Drs Patrice Piola and Carole Fogg (Epicentre, Uganda); Prof Halidou Tinto (Centre Muraz, Burkina Faso); Dr Ishag Adam (New Haifa Hospital, Sudan); Dr Isabela Ribeiro (DNDi, Brazil)
Almost all antimalarials studied to date have altered kinetic properties during pregnancy. In general, the drug levels obtained in the blood of pregnant women are significantly reduced compared to those in non-pregnant women. It is very likely that these changes in the dispositions of the drugs translate into a lower efficacy in treating and preventing malaria during pregnancy. It is therefore essential to define precisely the correct dose that must be administered to pregnant women both for treatment and in IPTp regimens.Objectives
Primary: To establish the pharmacokinetic properties of the main antimalarial candidate drugs to be used in pregnancy.
Secondary: To study the pharmacological determinants of the parasitological responses to treatment and the tolerability of the various drug regimens in pregnant women.Methods
Studies on the pharmacokinetics (PK) and pharmacodynamics of antimalarial drugs were conducted with samples from studies in Thailand, Uganda, Senegal, Sudan, Kenya and Burkina Faso. The studies used population and rich PK methods to assess the following antimalarial drugs in pregnant women: artemisinin derivatives, piperaquine, quinine, amodiaquine, lumefantrine and mefloquine.Results and Conclusions
Important differences in the pharmacokinetic properties of lumefantrine were demonstrated, resulting in lower drug exposure in pregnant women compared to non-pregnant women and significantly lower drug exposures to all artemisinin components were also found in pregnant women. These altered exposures are likely the reason for high failure rates in pregnant women in South Asia. The developed models were used to test novel regimens and a 5-day treatment with artemether-lumefantrine might be more suitable in comparison to the standard 3-day regimen.
While the other drugs did not see reductions in exposure, the lower exposure to the artemisinin components could result in lower cure rates and the combined clinical effect needs to be evaluated.Impact
Results from a systematic review of antimalarial drug PK properties in studies among pregnant
women using data from these and other PK studies were presented to the WHO Evidence review Group on malaria in Pregnancy in 2017, who concluded the following:
- generally lower drug exposure to artemisinins, lumefantrine, piperaquine and sulphadoxine-pyrimethamine in pregnant women compared with non-pregnant women;
- contradictory results reported for chloroquine and pyrimethamine in pregnant women compared with non-pregnant women;
- no difference in drug exposure to amodiaquine, mefloquine and quinine in pregnant women compared to postpartum women; and
- that the clinical impact of the reported PK changes and dose optimization need to be established.
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Adam, I., et al. (2012). "Pharmacokinetics of piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria." Am J Trop Med Hyg 87(1): 35-40.
Hoglund, R. M., et al. (2012). "A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan." Malar J 11: 398.
McGready, R., et al. (2012). "Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects." Br J Clin Pharmacol 73(3): 467-477.
Tarning, J., et al. (2012). "Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy." Antimicrob Agents Chemother 56(11): 5764-5773.
Tarning, J., et al. (2012). "Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda." Malar J 11: 293.
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Tarning, J., et al. (2013). "Pharmacokinetic properties of artemether, dihydroartemisinin, lumefantrine, and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in Uganda." Antimicrob Agents Chemother 57(10): 5096-5103.
Kloprogge, F., et al. (2014). "Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda." J Antimicrob Chemother 69(11): 3033-3040.
Kloprogge, F., et al. (2015). "Opposite malaria and pregnancy effect on oral bioavailability of artesunate - a population pharmacokinetic evaluation." Br J Clin Pharmacol 80(4): 642-653.
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