Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border

Abstract

Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an Emax model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].)

The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data

“…While resistance to artemisinin has emerged in South-East Asia [8] and a degree of resistance to the partner drugs exists in some parts of the world, both treatments remain highly effective in most African malariaendemic areas [9][10][11][12]. The pharmacokinetic properties of each drug are relatively well characterized: lumefantrine and its metabolite desbutyl-lumefantrine have terminal elimination half-lives of 1-10 days [1,[13][14][15][16], while desethylamodiaquine, the active metabolite of amodiaquine, has a half-life of 4-10 days [1,[17][18][19][20][21][22]. However, these estimates do not provide information on the duration of post-treatment prophylaxis which also depends on the pharmacodynamics of the drug.…”

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

“…Artemether-lumefantrine is a highly efficacious artemisinin-based combination therapy approved by WHO for use in the 2nd and 3rd trimesters of pregnancy. Previous studies have shown that the standard 3-day treatment in later pregnancy is associated with lower plasma concentrations of artemether, dihydroartemisinin (DHA), and lumefantrine and more rapid elimination of lumefantrine (5)(6)(7). Low lumefantrine plasma concentrations are associated with therapeutic failure in the treatment of falciparum malaria (8)(9)(10).…”

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

“…This may underpin the unsatisfactory low cure rates of artemether‐lumefantrine in this vulnerable group. A simultaneous population‐based PK drug‐metabolite modeling indicates suboptimal of artemether‐lumefantrine for P falciparum in this area, and increased treatment duration is proposed 168 . The study in Uganda, however, demonstrates comparable overall PK exposures to artemether, dihydroartemisinin, and lumefantrine during pregnancy, indicating no requirement of dose adjustment 169 .…”