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This study re-evaluated contraceptive requirements for women taking miltefosine, the only oral leishmaniasis treatment, using pharmacokinetic modeling across 8,863 women from India, East Africa, and Brazil. Researchers found that shorter contraceptive durations than currently recommended may be safe: three months for 14-day treatment regimens, four months for 21-28 day regimens, and five months for 42-day regimens, all counted from treatment start. The analysis used drug exposure modeling and a safety threshold derived from animal studies with a 10-fold safety margin to determine when residual drug levels fall below concerning levels for fetal development.
Why it matters
Current guidelines require contraception for five months after treatment completion, which can delay treatment or create barriers to care for women with leishmaniasis. Shortening the required contraceptive period, particularly for the common 14-day regimen, could improve treatment access while maintaining fetal safety, especially important in resource-limited endemic regions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Introduction Miltefosine 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. Methods Virtual 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-day 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. Results The 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. Conclusion An 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.