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

Ric Price, A Uhlemann, M Vanvugt, A Brockman, R Hutagalung, Shalini Nair, D Nash, Pratap Singhasivanon, Tim Anderson, Sanjeev Krishna, N WHITE, F NOSTEN

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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. � 2006 by the Infectious Diseases Society of America. All rights reserved.
    Original languageEnglish
    Pages (from-to)1570-1577
    Number of pages8
    JournalClinical Infectious Diseases
    Volume42
    Issue number11
    Publication statusPublished - 2006

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    Price, R., Uhlemann, A., Vanvugt, M., Brockman, A., Hutagalung, R., Nair, S., Nash, D., Singhasivanon, P., Anderson, T., Krishna, S., WHITE, N., & NOSTEN, 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.