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

Clin Infect Dis. 2006 Jun 1;42(11):1570-7. doi: 10.1086/503423. Epub 2006 Apr 26.

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 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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • ATP-Binding Cassette Transporters
  • Antimalarials
  • Artemisinins
  • Ethanolamines
  • Fluorenes
  • Protozoan Proteins
  • mdr gene protein, Plasmodium
  • Artemether
  • Lumefantrine