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

Thomas P C Dorlo, Suman Rijal, Bart Ostyn, Peter J de Vries, Rupa Singh, Narayan Bhattarai, Surendra Uranw, Jean-Claude Dujardin, Marleen Boelaert, Jos H Beijnen, Alwin D R Huitema

Research output: Contribution to journalA1: Web of Science-article

Abstract

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.

Original languageEnglish
JournalJournal of Infectious Diseases
Volume210
Issue number1
Pages (from-to)146-153
ISSN0022-1899
DOIs
Publication statusPublished - 2014

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