Translationele farmacokinetische modellering en simulatie om de duur van anticonceptie te bepalen na behandeling met miltefosine

OBJECTIVE To provide a rational approach for suggesting durations of contraceptive cover for various miltefosine regimens. 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. DESIGN AND 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 g-d/L. 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. CONCLUSION 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.