Frank Kloprogge (1,2), Rose McGready (1,2,3), Warunee Hanpithakpong (2), Siribha Apinan (2), Nicholas P.J. Day (1,2), Nicholas J. White (1,2) , François Nosten (1,2,3), Joel Tarning (1,2)
(1) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom, (2) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (3) Shoklo Malaria Research Unit, Mae Sot, Thailand
Objectives: Artemether-lumefantrine is the most widely used ACT in the world, but its efficacy in the treatment of malaria in pregnancy in a low transmission setting along the Thailand-Myanmar border has been disappointing. Lumefantrine plasma concentrations on day 7 are a commonly used pharmacokinetic endpoint to assess therapeutic responses however recent studies suggested that the main active metabolite, desbutyl-lumefantrine, might be correlated better to efficacy. The objective of the current analysis was to evaluate the pharmacokinetic and pharmacodynamic properties of lumefantrine and desbutyl-lumefantrine in pregnant women in Thailand with uncomplicated Plasmodium falciparum malaria.
Methods: Dense venous [1] and sparse capillary [2] lumefantrine and desbutyl-lumefantrine plasma concentration samples from 116 patients were evaluated simultaneously in a drug-metabolite model using NONMEM v7.2. Different absorption, distribution, variability, covariate and error models were assessed using the FOCE-I estimation method. Laplacian-I was used to model the time to recrudescent infection with an interval-censored time-to-event approach.
Results: A first-order absorption model with lag-time followed by two distribution compartments for lumefantrine and desbutyl-lumefantrine fitted the data adequately. A correction factor, at a population level, was implemented for the differences between the capillary and venous blood samples. Time to recrudescent malaria infections was best described using a Gompertz hazard model. Lumefantrine and desbutyl-lumefantrine realised a similar improvement in model fit when added as a traditional maximum effect function on the exponential baseline hazard. However, lumefantrine showed better predictive power compared to desbutyl-lumefantrine. A simultaneous lumefantrine and desbutyl-lumefantrine drug effect did not further improve the model.
Conclusions: The developed model described the pharmacokinetic and pharmacodynamic data well. Lumefantrine and desbutyl-lumefantrine concentrations were highly correlated and could be used interchangeably to predict the time to recrudescent malaria but lumefantrine realised a better predictive power. This model will be highly useful in informing the selection of new artemether-lumefantrine dose strategies in pregnant patients with malaria.
References:
[1] McGready, R., et al., The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol, 2006. 62(12): p. 1021-31.
[2] Tarning, J., et al., Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother, 2009. 53(9): p. 3837-46.
Reference: PAGE 22 () Abstr 2828 [www.page-meeting.org/?abstract=2828]
Poster: Infection