Division Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Antimicrob Chemother. 2012 Aug;67(8):1996-2004. doi: 10.1093/jac/dks164. Epub 2012 May 10.
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.
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.
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.
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.
米替福新治疗内脏利什曼病（VL）时，由于其潜在的致畸性而受到阻碍。在停止潜在致畸药物治疗后，具有生育能力的女性需要多长时间的避孕措施仍存在争议。本研究的目的是提供一种合理的方法，为各种米替福新方案建议避孕措施的持续时间。
使用动物到人类剂量转换得出人类生殖安全性阈值暴露限值。缺乏米替福新在女性中的药代动力学（PK）数据；使用先前开发的群体 PK 模型和全面的人体测量数据集，模拟接受米替福新治疗 5、7、10 或 28 天的印度女性 VL 患者的 PK 数据。使用超过阈值的米替福新暴露的概率来评估各种方案治疗后的避孕措施的持续时间。
对 465 名有生育能力的印度女性 VL 患者进行了 PK 数据模拟，中位年龄为 25 岁（IQR 16-31 岁），中位体重为 38 公斤（IQR 34-42 公斤）。从动物生殖毒性研究中，得出了人类生殖安全性阈值暴露限值为 24.5μg·day/mL。对于标准的 28 天方案，治疗后避孕措施持续 4 个月，以及对于较短的方案，避孕措施持续 2 个月，超过阈值的米替福新暴露的“无保护”概率非常低（<0.2%）。
据我们所知，这是第一项基于动物到人类剂量转换为致畸药物提供避孕措施建议的研究。对于 28 天的米替福新方案，治疗后避孕措施可以延长至 4 个月，而对于所有较短的方案，2 个月可能就足够了。
