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J Infect Dis. 2014 Jul 1;210(1):146-53. Epub 2014 Jan 16.

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

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.

PMID:
24443541
DOI:
10.1093/infdis/jiu039
[Indexed for MEDLINE]

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