Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients

Abstract

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.

FIG. 1.

Visual predictive check of population pharmacokinetic model for miltefosine. The open dots present data for all analyzed study samples (n = 382) from 31 Dutch military personnel with cutaneous leishmaniasis (L. major) contracted in Afghanistan. All patients were treated with 50 mg of oral miltefosine three times daily for a total of 28 days. The gray area shows the 90% confidence interval of the model predictions; the dashed line displays the median predicted concentrations.

FIG. 2.

Observed concentrations versus individual (A) and model (B) predicted concentrations. The straight lines represent linear regression lines, while dotted lines represent lines of unity.

FIG. 3.

Conditional weighted residuals versus time (A) and versus model predicted concentrations (B).