Modelling lumefantrine PK/PD relationships in pregnant women

Each year, malaria infection during pregnancy is associated with 10,000 maternal deaths and accounts for up to 200,000 infant deaths in Africa. It can result in still birth, miscarriage, and severe anaemia in the mother and is linked to learning and developmental difficulties in the baby as it develops. WWARN’s Pharmacology team are exploring avenues to improve the efficacy of antimalarial drug use in pregnant women using pharmacokinetic and pharmacodynamic (PK/PD) modelling.

Recently the WWARN Pharmacology group and partners, published a study in the journal, Antimicrobial Agents and Chemotherapy, using PK/PD models to explore ways to enhance the efficacy of the commonly used antimalarial, artemether-lumefantrine (AL), in pregnant women and reduce the risk of treatment failures. The simulations acquired from the modelling suggest that cure rates in malaria infected pregnant women could be improved by prolonging the treatment regimen.

AL is the most widely used antimalarial treatment and is considered safe to treat pregnant women in the second and third trimester. Although it is safe to use, the number of women successfully cured using current recommended treatment regimens can vary from country to country. Cure rates with AL in pregnant women are lowest in Northwest Thailand, on the border with Myanmar, where there are high levels of antimalarial drug resistance.

“The key aim of this study was to assess the population pharmacokinetics and pharmacodynamics of lumefantrine in malaria infected pregnant women,” says Prof Joel Tarning, senior author of the study and Head of Pharmacometrics at WWARN. “From these simulations, we found that currently recommended dose regimens of artemether-lumefantrine work well in most populations, but may be less effective in pregnant patients on the Thai-Myanmar border where incidences of artemisinin drug resistance are high.”

The team developed a simultaneous pharmacokinetic drug-metabolite model and successfully linked this model to the therapeutic outcome using samples from 116 pregnant patients treated with lumefantrine on the Thai-Myanmar border. The model defined the PK/PD relationship and properties of lumefantrine and desbutyl-lumefantrine - the main metabolite of lumefantrine – to accurately assess the combined drug effect of both the parent compound and the metabolite.

“Pregnancy can alter the disposition, or pharmacokinetics, of a drug in the body, changing the drug exposure and thus possibly affecting treatment success,” says Dr Frank Kloprogge, first author of the study. “For these reasons, dosing recommendations for a non-pregnant adult do not necessarily reflect the dosing needs of pregnant woman. We are now trying to uncover how big a problem this is, while also trying to establish the optimal dosing regimen for pregnant women through modelling.”

Although, AL is still working well in most populations, these simulations show that pregnant women in the Thai-Myanmar border are at higher risk of treatment failure under current treatment guidelines. The continued use of the currently recommended doses of this combination therapy in pregnant women could result in the increased risk of drug failure and potentially, the further spread of drug resistant malaria parasites, especially on the Thai-Myanmar boarder.

“We need to undertake more research to confirm whether adjustments to AL dose regimens are needed for pregnant women,” adds Prof Tarning.

The team are using mathematical and statistical techniques to perform a comparison of drug exposures of other commonly used antimalarial treatments in non-pregnant adults, pregnant women, and infants to better understand how different factors such as weight, age, and pregnancy affect the pharmacokinetics of antimalarial drugs.

Publication details:

Frank Kloprogge et al. Lumefantrine and desbutyl-lumefantrine population pharmacokinetic-pharmacodynamic relationships in pregnant women with uncomplicated Plasmodium falciparum malaria on the Thailand-Myanmar border. Antimicrobial Agents and Chemotherapy (2015) Accepted manuscript posted online 3 August 2015, doi: 10.1128/AAC.00267-15