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Antimicrobial Agents and Chemotherapy, August 2008, p. 2855-2860, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00014-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Miltefosine in Old World Cutaneous Leishmaniasis Patients{triangledown}

Thomas P. C. Dorlo,1,2* Pieter P. A. M. van Thiel,2,3 Alwin D. R. Huitema,1 Ron J. Keizer,1 Henry J. C. de Vries,4 Jos H. Beijnen,1 and Peter J. de Vries2

Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands,1 Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands,2 Military Health Care Expertise Coordination Centre, Hilversum, The Netherlands,3 Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands4

Received 4 January 2008/ Returned for modification 9 March 2008/ Accepted 28 April 2008

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.

* Corresponding author. Mailing address: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. Phone: 31 20 512 4073. Fax: 31 20 512 4753. E-mail: thomas.dorlo{at}slz.nl

{triangledown} Published ahead of print on 2 June 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2855-2860, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00014-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Griewank, K., Gazeau, C., Eichhorn, A., von Stebut, E. (2010). Miltefosine Efficiently Eliminates Leishmania major Amastigotes from Infected Murine Dendritic Cells without Altering Their Immune Functions. Antimicrob. Agents Chemother. 54: 652-659 [Abstract] [Full Text]  
  • Soto, J., Rea, J., Valderrama, M., Toledo, J., Valda, L., Ardiles, J., Berman, J. (2009). Efficacy of Extended (Six Weeks) Treatment with Miltefosine for Mucosal Leishmaniasis in Bolivia. Am J Trop Med Hyg 81: 387-389 [Abstract] [Full Text]  


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