RESUMEN
BACKGROUND: Artemether-lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the dose-response relationship between coadministration of fat and relative lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption. METHOD: We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration-time curve (AUC) for lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3- to 4-week washout period in-between. RESULTS: A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat). CONCLUSIONS: Coadministration of artemether-lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.
Asunto(s)
Antimaláricos/farmacocinética , Etanolaminas/farmacocinética , Fluorenos/farmacocinética , Leche de Soja/administración & dosificación , Absorción , Administración Oral , Adulto , Antimaláricos/administración & dosificación , Área Bajo la Curva , Combinación Arteméter y Lumefantrina , Artemisininas/administración & dosificación , Disponibilidad Biológica , Estudios Cruzados , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Ayuno , Femenino , Fluorenos/administración & dosificación , Interacciones Alimento-Droga , Humanos , Lumefantrina , Malaria Falciparum/prevención & control , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether-lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. METHODS: In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration-time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. RESULTS: Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC((0-->infinity)) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114-5781) microg/ml h, compared with 432 (308-992) microg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84-100) in the six-dose arm and 85% (70-100) in the three-dose arm (P = 0.3). CONCLUSION: Artemether-lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat.
Asunto(s)
Antimaláricos/farmacocinética , Artemisininas/administración & dosificación , Etanolaminas/administración & dosificación , Etanolaminas/farmacocinética , Fluorenos/administración & dosificación , Fluorenos/farmacocinética , Malaria Falciparum/tratamiento farmacológico , Absorción , Administración Oral , Adolescente , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/sangre , Área Bajo la Curva , Combinación Arteméter y Lumefantrina , Esquema de Medicación , Combinación de Medicamentos , Resistencia a Múltiples Medicamentos , Etanolaminas/sangre , Femenino , Fluorenos/sangre , Humanos , Lumefantrina , Malaria Falciparum/sangre , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Early diagnosis and treatment with artesunate-mefloquine combination therapy (MAS) have reduced the transmission of falciparum malaria dramatically and halted the progression of mefloquine resistance in camps for displaced persons along the Thai-Burmese border, an area of low and seasonal transmission of multidrug-resistant Plasmodium falciparum. We extended the same combination drug strategy to all other communities (estimated population 450,000) living in five border districts of Tak province in northwestern Thailand. METHODS AND FINDINGS: Existing health structures were reinforced. Village volunteers were trained to use rapid diagnostic tests and to treat positive cases with MAS. Cases of malaria, hospitalizations, and malaria-related deaths were recorded in the 6 y before, during, and after the Tak Malaria Initiative (TMI) intervention. Cross-sectional surveys were conducted before and during the TMI period. P. falciparum malaria cases fell by 34% (95% confidence interval [CI], 33.5-34.4) and hospitalisations for falciparum malaria fell by 39% (95% CI, 37.0-39.9) during the TMI period, while hospitalisations for P. vivax malaria remained constant. There were 32 deaths attributed to malaria during, and 22 after the TMI, a 51.5% (95% CI, 39.0-63.9) reduction compared to the average of the previous 3 y. Cross-sectional surveys indicated that P. vivax had become the predominant species in Thai villages, but not in populations living on the Myanmar side of the border. In the displaced persons population, where the original deployment took place 7 y before the TMI, the transmission of P. falciparum continued to be suppressed, the incidence of falciparum malaria remained low, and the in vivo efficacy of the 3-d MAS remained high. CONCLUSIONS: In the remote malarious north western border area of Thailand, the early detection of malaria by trained village volunteers, using rapid diagnostic tests and treatment with mefloquine-artesunate was feasible and reduced the morbidity and mortality of multidrug-resistant P. falciparum.
Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/diagnóstico , Malaria Falciparum/tratamiento farmacológico , Mefloquina/uso terapéutico , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Adulto , Anciano , Artesunato , Estudios Transversales , Quimioterapia Combinada , Diagnóstico Precoz , Femenino , Mortalidad Hospitalaria , Hospitalización , Humanos , Incidencia , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Malaria Vivax/diagnóstico , Malaria Vivax/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud , Pruebas de Sensibilidad Parasitaria , Embarazo , Complicaciones Parasitarias del Embarazo/diagnóstico , Prevalencia , Refugiados , Tailandia/epidemiología , Clima TropicalRESUMEN
BACKGROUND: Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). METHODS: On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. RESULTS: All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. CONCLUSIONS: The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.