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 (
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.
Dorlo, T.P.C.; Balasegaram, M.; Lima, M.A.; de Vries, P.J.; Beijnen, J.H.; Huitema, A.D.R. Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine. Journal of Antimicrobial Chemotherapy (2012) 67 (8) 1996-2004. [DOI: 10.1093/jac/dks164]