Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria |
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| Authors: | Joel Tarning Rose McGready Niklas Lindegardh Elizabeth A. Ashley Mupawjay Pimanpanarak Benjamas Kamanikom Anna Annerberg Nicholas P. J. Day Kasia Stepniewska Pratap Singhasivanon Nicholas J. White Fran?ois Nosten |
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| Affiliation: | Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,1. Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom,2. Shoklo Malaria Research Unit, Mae Sot, Thailand,3. Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand4. |
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| Abstract: | Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.Pregnancy has considerable effects on the pharmacokinetic properties of many of the drugs used to treat uncomplicated Plasmodium falciparum malaria. Whereas blood chloroquine and quinine concentrations are relatively unaffected (1, 25), artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, and cycloguanil concentrations are all reduced in later pregnancy (14, 30-33). The reductions are often substantial, and as a result, antimalarial cure rates in pregnancy for any given antimalarial drug tend to be lower (24, 34). Unfortunately, pregnant women are especially vulnerable to malaria and the fetus is adversely affected.The fixed combination of artemether and lumefantrine is the result of research undertaken by Chinese scientists and has become the most widely used coformulated artemisinin-based combination therapy (ACT). Artemether-lumefantrine has proved effective (cure rates, >97%) and safe in adults and children in trials conducted throughout the areas of the world affected by malaria (2, 13, 15, 20, 23, 35, 43, 44, 59). There is a reluctance to prescribe new drugs to pregnant women, and there have been concerns over the safety of artemisinin derivatives in early pregnancy. The current assessment of the benefits compared with the potential risks suggests that the artemisinin derivatives should be used to treat uncomplicated P. falciparum malaria in the second and third trimesters, as a result of documented experience with the treatment of more than 1,500 pregnant women (9, 40, 56). Evaluation of the new fixed ACTs is lagging behind these recommendations (53).A recent preliminary study with 13 pregnant women with frequent venous plasma sampling for pharmacokinetic analysis showed that the levels of artemether, dihydroartemisinin, and lumefantrine exposure were lower in this group than in nonpregnant adult patients in the same area (32). The maximum concentration (Cmax) of dihydroartemisinin (the principal metabolite of artemether) and total drug exposure (the area under the concentration-time curve from time zero to 8 h [AUC0-8]) were 20% and 40% lower, respectively, in pregnant patients than in nonpregnant patients. The level of exposure to lumefantrine after the last dose (the AUC from 60 h to infinity [AUC60-∞]) was 6% (90% confidence interval [CI], 5 to 12%) lower in pregnant patients than in nonpregnant patients, but because elimination was more rapid, later exposure (AUC from 120 h to infinity [AUC120-∞]) was 49% (95% CI, 28 to 91%) lower in pregnant patients than in nonpregnant patients (32). The total exposure to lumefantrine has previously been shown to be a good predictor of outcome in the same population (55), although it is believed that the later concentrations in the third and subsequent parasite life cycles (>4 days) may be the main determinant (52). The day 7 concentrations of lumefantrine correlate well with total drug AUCs, and this measurement has therefore been used as a measure of drug exposure in clinical studies of artemether-lumefantrine (55). Indeed, there are reasons to believe that this may be a better determinant of the therapeutic response than the total AUC for many antimalarial drugs used today (54). Venous plasma lumefantrine concentrations of 175 ng/ml (42) and 280 ng/ml (11, 12) at day 7 have been suggested to be cutoffs below which there is a 25% and a 50% risk of therapeutic failure, respectively, in this area. A plasma lumefantrine concentration of >500 ng/ml on day 7 is associated with a treatment success rate of >90% (11, 55). A high proportion (38%) of the pregnant patients in the preliminary pharmacokinetic study described previously had day 7 lumefantrine concentrations below 280 ng/ml, suggesting that lower concentrations on day 7 may result in lower cure rates in this vulnerable group (32).The main objective of the study described here was to investigate the pharmacokinetic properties of lumefantrine by use of a population-based modeling approach in pregnant women treated with the standard dose of artemether-lumefantrine. |
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