The relationship between capillary and venous concentrations of the antimalarial drug lumefantrine (benflumetol)

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...

Section: Methodsmentioning

confidence: 99%

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

Tärning

McGready

Lindegårdh

et al. 2009

114

“…Additionally, from a subset of 26 patients, 91 pairs of capillary and venous blood samples were collected to test for differences in concentration due to the method of blood sampling (13). Venous blood samples of 4 ml each were withdrawn by venipuncture into heparinized tubes and centrifuged without delay at 1,000 ϫ g for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…The model was refitted and modified by adding the less frequently sampled capillary concentration data provided from patients at the Mae La clinic. Pooling of capillary and venous blood sample data was considered appropriate, as there is no significant difference between capillary lumefantrine and venous lumefantrine concentrations (13).…”

Section: Methodsmentioning

confidence: 99%

“…This study combined a conventional inpatient pharmacokinetic study of adults with a population-based community study of patients of all ages and in whom recently validated capillary blood sampling was used (13). The objective of the pharmacokinetic investigation was to characterize the factors which affect blood lumefantrine concentrations and thus the therapeutic response.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and Pharmacodynamics of Lumefantrine (Benflumetol) in Acute Falciparum Malaria

Ezzet

Vugt

Nosten

et al. 2000

Self Cite

303

259

The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) g/ml after regimen A, 9.0 (1.1 and 19.8) g/ml after regimen B, and 8 (1.4 and 17.4) g/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 g/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.

“…Artemether is metabolized in the liver by the isoenzyme CYP3A4, to its active metabolite dihydroartemisinin (DHA), with peak plasma concentration being reached around 2 to 3 h after oral administration (4); elimination half-life is estimated at approximately 1 h. There is thus only limited opportunity for DHA to participate in drug-drug interactions. Lumefantrine is partially metabolized to desbutyl-lumefantrine, predominantly through CYP3A4, reaching peak plasma levels approximately 10 h after oral administration, and is then cleared slowly, showing a terminal half-life of 4 to 6 days in P. falciparum malaria cases (5)(6)(7)(8)(9). Oral bioavailability of lumefantrine is variable and highly dependent on administration with fatty foods (5,9,10).…”

mentioning

confidence: 99%

HIV-Positive Nigerian Adults Harbor Significantly Higher Serum Lumefantrine Levels than HIV-Negative Individuals Seven Days after Treatment for Plasmodium falciparum Infection

Chijioke-Nwauche

Wyk

Nwauche

et al. 2013

e Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic Plasmodium falciparum infections by microscopy. Post hoc PCR analysis confirmed the presence of P. falciparum in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (P ‫؍‬ 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on in vivo malaria treatment outcomes in HIV-infected patients are thus needed.