Pharmacokinetic study of artemether–lumefantrine given once daily for the treatment of uncomplicated multidrug‐resistant falciparum malaria

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemetherlumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallelgroup study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n ‫؍‬ 91) and crushed (n ‫؍‬ 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C max ) for the different body weight groups, with overall means of 175 ؎ 168 and 190 ؎ 168 ng/ml, respectively, for artemether and 64.7 ؎ 58.1 and 63.7 ؎ 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C max were 6.3 g/ml (dispersible tablet) and 7.7 g/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 g ⅐ h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C max and parasite clearance time or between the lumefantrine C max and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria.Artemisinin-based combination therapies (ACTs) are currently the best available treatments for uncomplicated Plasmodium falciparum malaria because of their fast action, reliable efficacy, good safety profile, and potential to lower the emergence and spread of drug resistance (2,6,18,20). Artemetherlumefantrine (A-L; Coartem) was the first fixed-dose ACT prequalified by the World Health Organization (WHO) and has subsequently been adopted by many countries in sub-Saharan Africa as first-line treatment for uncomplicated P. falciparum malaria (26). The recommended 6-dose regimen of A-L, twice a day for 3 days, has been proven to be efficacious and safe in both infants and children weighing 5 to 35 kg and adults weighing Ͼ35 kg (11,13,15,17).In young children, A-L is usually administered as a crushed tablet (CT). In an effort to ease administration of A-L, a sweetened cherry-flavored A-L dispersible tablet (DT) formulation containing the same amounts of artemether and lumefantrine as the standard tablet was developed. Pharmacokinetic assessments were performed withi...

Section: Discussionsupporting

confidence: 56%

Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria

Djimdé

Tekete

Abdulla

et al. 2011

“…The simulations suggested that a 100% dose increase would achieve the target day 7 plasma lumefantrine concentrations in 95% of these women with a normal 3-day regimen. This may not achieve its objective because of the dose-limited absorption of lumefantrine (5). Therefore, we suggest the use of a 5-day instead of a 3-day course of artemether-lumefantrine in later pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…4. No simulations of higher-dose regimens are shown because of the dose-dependent oral absorption of lumefantrine (5,12). The duration of artemether and dihydroartemisinin exposure is assumed to last for approximately 6 h after each dose (i.e., three half-lives).…”

Section: Dose Regimen Simulationsmentioning

confidence: 99%

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

Tärning

McGready

Lindegårdh

et al. 2009

Self Cite

114

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)(31)(32)(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, Ͼ97%) 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 curr...

“…Various therapeutic thresholds have been reported for the day 7 lumefantrine concentration, ranging between 175 and 500 ng/ml, depending on the prevalence of resistance and the method used for determining this threshold; of these, 280 ng/ml is the most widely cited (3,12,13,23,27,28,41). Patients with uncomplicated malaria with day 7 lumefantrine concentrations below these concentrations are potentially at increased risk of treatment failure (3,12,13,23,27,28,41). Therapeutic pharmacokinetic thresholds have yet to be defined for the artemisinin derivatives.…”

mentioning

confidence: 99%

Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients

Kredo

Mauff

Walt

et al. 2011

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P ‫؍‬ 0.0002).