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

Rie N. Price, Anne Catrin Uhlemann, Michela Van Vugt, Al Brockman, Robert Hutagalung, Shalini Nair, Denae Nash, Pratap Singhasivanon, Tim J.C. Anderson, Sanjeev Krishna, Nicholas J. White, François Noston

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    Abstract

    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 concentration50 (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.

    Original languageEnglish (US)
    Pages (from-to)1570-1577
    Number of pages8
    JournalClinical Infectious Diseases
    Volume42
    Issue number11
    DOIs
    StatePublished - Jun 1 2006

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    ASJC Scopus subject areas

    • Microbiology (medical)
    • Infectious Diseases

    Cite this

    Price, R. N., Uhlemann, A. C., Van Vugt, M., Brockman, A., Hutagalung, R., Nair, S., Nash, D., Singhasivanon, P., Anderson, T. J. C., Krishna, S., White, N. J., & Noston, F. (2006). Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria. Clinical Infectious Diseases, 42(11), 1570-1577. https://doi.org/10.1086/503423