Title
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Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure
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Author
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Abstract
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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. |
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Language
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English
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Source (journal)
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The journal of infectious diseases. - Chicago, Ill.
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Publication
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Chicago, Ill.
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2014
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ISSN
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0022-1899
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DOI
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10.1093/INFDIS/JIU039
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Volume/pages
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210
:1
(2014)
, p. 146-153
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ISI
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000339670800017
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Full text (Publisher's DOI)
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