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      Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.

      Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

      ATP-Binding Cassette Transporters, genetics, Adolescent, Adult, Animals, Antimalarials, therapeutic use, Artemisinins, administration & dosage, Child, Child, Preschool, Drug Administration Schedule, Drug Resistance, Drug Therapy, Combination, Ethanolamines, blood, Female, Fluorenes, Humans, Malaria, Falciparum, drug therapy, Male, Plasmodium falciparum, drug effects, Polymorphism, Single Nucleotide, Protozoan Proteins

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          Abstract

          Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). 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. 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. 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.

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          Journal
          16652314
          4337983
          10.1086/503423

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