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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

102 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)146-153
Aantal pagina's8
TijdschriftThe Journal of infectious diseases
Volume210
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 1 jul. 2014
Extern gepubliceerdJa

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