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1: Antimicrob Agents Chemother. 2008 Aug;52(8):2855-60. Epub 2008 Jun 2.
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Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients.

Dorlo TP, van Thiel PP, Huitema AD, Keizer RJ, de Vries HJ, Beijnen JH, de Vries PJ.

Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. thomas.dorlo@slz.nl

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.

PMID: 18519729 [PubMed - in process]

PMCID: PMC2493105