desbutylbenflumetol and Malaria--Falciparum

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child, Preschool; Dose-Response Relationship, Drug; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Models, Chemical; Pregnancy

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].).

Topics: Adolescent; Adult; Antimalarials; Computer Simulation; Drug Administration Schedule; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Models, Statistical; Myanmar; Plasmodium falciparum; Pregnancy; Recurrence; Thailand; Treatment Outcome

This in vitro study was conducted to assess the blood schizontocidal activity of desbutyl-benflumetol (DBB), a new benzindene derivative, retinol and a combination of both compounds. The tests were carried out according to the methodology of the WHO standard test Mark II, measuring the drug-dependent inhibition of schizont maturation, and using 43 fresh isolates of Plasmodium falciparum from northwestern Thailand, an area with established multidrug-resistance. DBB and retinol showed a mean 50% effective concentration (EC-50) of 3.73 nM and 466.86 nM and 90% effective concentration (EC-90) of 19.83 nM and 5531.69 nM respectively. The combination of DBB and 3.50 muM retinol showed strong inhibition of schizont maturation, with an EC-90 for DBB of 0.67 nM. At the therapeutically relevant EC-99, the combination was about 10 times more effective than expected, suggesting that retinol potentiated the effect of DBB. A concentration of 3.50 muM retinol corresponds to the 95th percentile of the physiological serum levels. It is well known that retinol levels are significantly decreased in acute falciparum malaria. Supplementation with retinol during malaria treatment may improve the therapeutic results of blood schizontocides of the fluorene class.

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance; Drug Synergism; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Parasitic Sensitivity Tests; Plasmodium falciparum; Treatment Outcome; Vitamin A; Vitamins

The sensitivity of Plasmodium falciparum against artemisinin, monodebutyl-benflumetol (DBB) and a 1:3 m/m combination of both compounds was assessed in 51 fresh parasite isolates. Although a comparison between fully inhibitory concentrations (GMCOC) of artemisinin alone (63.33 nM), DBB alone (50.15 nM) and the combination (23.92 nM) indicated significant synergism between artemisinin and DBB, this was less evident when comparing the log-probit regressions. Moreover, the geometric mean values of the fractional inhibitory concentrations (SFIC) showed a rising tendency with increasing EC level. In a study comprising 24 fresh isolates of P. falciparum, the interaction between DBB and proguanil was explored with a 3:1 m/m combination of both compounds. Proguanil alone showed weak blood schizontocidal activity. The log-probit regressions indicated higher activity of the combination as compared to DBB alone. The SFIC values indicated moderate synergism between DBB and proguanil that could be an advantage in an eventual therapeutic and prophylactic use of DBB.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Drug Synergism; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitic Sensitivity Tests; Plasmodium falciparum; Proguanil; Thailand; Young Adult