title: Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine.
abstract: OBJECTIVE
  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.
authors.affiliation: Division Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. t.p.dorlo@amc.nl
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
authors.forename: Manica
authors.initials: M
authors.lastname: Balasegaram
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Lima
authors.forename: Peter J
authors.initials: PJ
authors.lastname: de Vries
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003270:Contraceptive Agents / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007194:India; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D015233:Models, Statistical; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013723:Teratogens / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000981:Antiprotozoal Agents; D003270:Contraceptive Agents; D013723:Teratogens; D010767:Phosphorylcholine; C039128:miltefosine