Pharmacokinetics

Project Coordinator:

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)

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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.