Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure

J Infect Dis. 2014 Jul 1;210(1):146-53. doi: 10.1093/infdis/jiu039. Epub 2014 Jan 16.


Background: Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL.

Methods: Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure.

Results: The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure.

Conclusions: Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antiprotozoal Agents / administration & dosage*
  • Antiprotozoal Agents / pharmacokinetics*
  • Blood Chemical Analysis
  • Child
  • Child, Preschool
  • Chromatography, Liquid
  • Humans
  • Infant
  • Leishmaniasis, Visceral / drug therapy*
  • Male
  • Middle Aged
  • Nepal
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacokinetics
  • Tandem Mass Spectrometry
  • Treatment Failure
  • Young Adult


  • Antiprotozoal Agents
  • Phosphorylcholine
  • miltefosine