Publication
Title
Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure
Author
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 VL patients. Methods. Miltefosine steady-state blood concentrations at the end of treatment were analyzed using LC-MS/MS. A population pharmacokinetic-pharmacodynamic analysis was performed using non-linear fixed-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 the blood concentration exceeded the threshold of 10x the EC50 of miltefosine (median 30.2 days) was significantly associated with treatment failure: a decrease of this measure of miltefosine exposure with 1 day was associated with a 1.08 times (95% CI 1.01-1.17) increased odds of treatment failure. Conclusions. Achieving sufficient miltefosine exposure is a significant and critical factor for VL treatment success, which urges the evaluation of 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.
Language
English
Source (journal)
The journal of infectious diseases. - Chicago, Ill.
Publication
Chicago, Ill. : 2014
ISSN
0022-1899
Volume/pages
210:1(2014), p. 146-153
ISI
000339670800017
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 07.02.2014
Last edited 08.10.2017