Pharmacokinetics of miltefosine in old world cutaneous leishmaniasis patients

Thomas P.C. Dorlo, Pieter P.A.M. Van Thiel, Alwin D.R. Huitema, Ron J. Keizer, Henry J.C. De Vries, Jos H. Beijnen, Peter J. De Vries

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139 Citaten (Scopus)

Samenvatting

The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the last week of treatment (days 22 to 28) was 30,800 ng/ml. The maximum duration of follow-up was 202 days after the start of treatment. All analyzed samples contained a concentration above the LLOQ. Miltefosine is eliminated from the body much slower than previously thought and is therefore still detectable in human plasma samples taken 5 to 6 months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond 5 months after treatment might contribute to the selection of resistant parasites, and moreover, the measures for preventing the teratogenic risks of miltefosine treatment should be reconsidered.

Originele taal-2Engels
Pagina's (van-tot)2855-2860
Aantal pagina's6
TijdschriftAntimicrobial Agents and Chemotherapy
Volume52
Nummer van het tijdschrift8
DOI's
StatusGepubliceerd - aug. 2008
Extern gepubliceerdJa

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