Female contraceptive cover duration for miltefosine-containing regimens for the treatment of women with leishmaniasis
- 1Department of Pharmacy, Uppsala University, Uppsala, Sweden
Abstract
IntroductionMiltefosine is the only approved oral antileishmanial agent, but its use in women of childbearing potential (WOCBP) is restricted due to preclinical teratogenicity. Current labeling recommends contraception during treatment and for at least five months thereafter, based solely on its long terminal elimination half-life. This study re-evaluated the required contraceptive duration using an exposure margin-based approach.
MethodsVirtual populations were generated from anthropometric data of 382 Indian, 4,462 Eastern African, and 4,019 Brazilian WOCBP with leishmaniasis. Published population pharmacokinetic models were used to simulate miltefosine exposure following 14-42 days regimens for visceral leishmaniasis (VL), post-kala-azar dermal leishmaniasis (PKDL), and cutaneous leishmaniasis (CL). A developmental safety exposure threshold was derived from the rat no-observed-adverse-effect level (0.6 mg/kg/day for 10 days) and adjusted using a 10-fold safety margin. Contraceptive durations resulting in median residual post-contraception exposure (AUCEOC-{infty}) below this threshold were considered supportive of contraceptive discontinuation.
ResultsThe developmental safety exposure threshold was estimated at 2.5 mg{middle dot}day/L. Despite pharmacokinetic differences across geographical regions and disease manifestations, required minimum contraceptive durations were consistent: three months from treatment initiation for the 14-day regimen, four months for 21- and 28-day regimens, and five months for the 42-day regimen. For the 14-day regimen, a single dose of a long-acting injectable contraceptive administered at treatment initiation would provide sufficient coverage.
ConclusionAn exposure margin-based approach supports shorter contraceptive durations than current recommendations. For the 14-day VL regimen, three months of contraception may provide a practical alternative to current labeling.
Related
- Persistent myeloid cell reprogramming despite miltefosine treatment in leishmania-infected macaques
- Application Value and Cognitive Challenges of PET/CT in the Diagnosis and Treatment of Visceral Leishmaniasis: A Retrospective Single-Center Case Series and Literature Review
- Nano-Based Sodium Stibogluconate for Treatment of Cutaneous Leishmaniasis Caused by Leishmania major in Male Mice.
- Sub-national estimates of visceral leishmaniasis and optimisation of geographical accessibility to treatment centres in Kenya
- CD4+ and CD8+ lymphocyte responses and cytokine profiles in visceral leishmaniasis patients following effective treatment in distinct transmission settings in Bihar, India
BibTeX
@misc{chu2026female,
title = {{Female contraceptive cover duration for miltefosine-containing regimens for the treatment of women with leishmaniasis}},
author = {W.-Y. Chu and F. Alves and T. P. C. Dorlo},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26360682},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26360682v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Female contraceptive cover duration for miltefosine-containing regimens for the treatment of women with leishmaniasis
AU - W.-Y. Chu
AU - F. Alves
AU - T. P. C. Dorlo
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26360682
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26360682v1
AB - IntroductionMiltefosine is the only approved oral antileishmanial agent, but its use in women of childbearing potential (WOCBP) is restricted due to preclinical teratogenicity. Current labeling recommends contraception during treatment and for at least five months thereafter, based solely on its long terminal elimination half-life. This study re-evaluated the required contraceptive duration using an exposure margin-based approach. MethodsVirtual populations were generated from anthropometric data of 382 Indian, 4,462 Eastern African, and 4,019 Brazilian WOCBP with leishmaniasis. Published population pharmacokinetic models were used to simulate miltefosine exposure following 14-42 days regimens for visceral leishmaniasis (VL), post-kala-azar dermal leishmaniasis (PKDL), and cutaneous leishmaniasis (CL). A developmental safety exposure threshold was derived from the rat no-observed-adverse-effect level (0.6 mg/kg/day for 10 days) and adjusted using a 10-fold safety margin. Contraceptive durations resulting in median residual post-contraception exposure (AUCEOC-{infty}) below this threshold were considered supportive of contraceptive discontinuation. ResultsThe developmental safety exposure threshold was estimated at 2.5 mg{middle dot}day/L. Despite pharmacokinetic differences across geographical regions and disease manifestations, required minimum contraceptive durations were consistent: three months from treatment initiation for the 14-day regimen, four months for 21- and 28-day regimens, and five months for the 42-day regimen. For the 14-day regimen, a single dose of a long-acting injectable contraceptive administered at treatment initiation would provide sufficient coverage. ConclusionAn exposure margin-based approach supports shorter contraceptive durations than current recommendations. For the 14-day VL regimen, three months of contraception may provide a practical alternative to current labeling.
ER -