Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine

J Antimicrob Chemother. 2012 Aug;67(8):1996-2004. doi: 10.1093/jac/dks164. Epub 2012 May 10.


Objectives: Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens.

Methods: A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens.

Results: PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens.

Conclusions: To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antiprotozoal Agents / administration & dosage
  • Antiprotozoal Agents / adverse effects
  • Antiprotozoal Agents / pharmacokinetics*
  • Contraceptive Agents / administration & dosage*
  • Female
  • Humans
  • India
  • Leishmaniasis, Visceral / drug therapy
  • Models, Statistical
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / adverse effects
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacokinetics
  • Teratogens / pharmacokinetics*
  • Time Factors
  • Young Adult


  • Antiprotozoal Agents
  • Contraceptive Agents
  • Teratogens
  • Phosphorylcholine
  • miltefosine