Wendy Chu 1, Thomas Dorlo 1
1 Department of Pharmacy, Uppsala University (Uppsala, Sweden)
Introduction: Miltefosine is the only approved oral therapy for leishmaniasis and remains a key treatment for visceral leishmaniasis (VL), post-kala-azar dermal leishmaniasis (PKDL), and cutaneous leishmaniasis (CL). However, its use in women of childbearing potential is restricted due to preclinical evidence of teratogenicity. Based on the conventional assumption that near-complete elimination occurs after five terminal half-lives, a 5-month period of contraception after treatment completion is recommended [1]. In clinical practice, this often results in a total contraceptive duration of approximately 6-9 months from treatment initiation, depending on treatment length. This empirically derived, terminal half-life-based recommendation does not incorporate exposure-toxicity relationships and may create unnecessary barriers to treatment access and clinical trial participation in endemic regions. In light of recent clinical trials and anticipated updates to the WHO treatment guidelines for VL and PKDL, which support shortened miltefosine-containing combination regimens (14 days for VL and 42 days for PKDL in Eastern Africa; and 21 days for PKDL in India), it is timely to re-evaluate the required total contraceptive duration using a data driven, exposure-based framework aligned with the science-based principles outlined in the ICH S5 guideline and recent EFPIA-PDEG consensus recommendations [2,3].
Objectives: This framework integrates preclinical reproductive toxicity no observed adverse effect level (NOAEL) data with human population pharmacokinetic simulations informed by anthropometric datasets from real-world Indian and Eastern African female VL cohorts. Using this approach, we estimated the minimum required total contraceptive duration across clinically relevant miltefosine-containing regimens, with the aim of optimizing reproductive safety while minimizing unnecessary barriers to access effective miltefosine treatment.
Methods: Demographic data from 382 Indian and 4,462 Eastern African (Ethiopia, Kenya, Sudan, Uganda, and South Sudan) females of childbearing potential with VL were compiled to generate virtual populations of 10,000 individuals per region using conditional distribution modeling. Miltefosine plasma concentration-time profiles were simulated using previously developed population pharmacokinetic models for VL and PKDL, in which 15% lower miltefosine bioavailability was characterized in the Eastern African population [4]. Regimens assessed included 14 and 28 days for VL and 21, 28, and 42 days for PKDL. A reproductive safety exposure threshold was defined based on the rat NOAEL of 0.6 mg/kg/day for 10 days [5], with systemic exposure (AUC₀-∞) derived using published miltefosine clearance in rat and applying an additional 10-fold safety margin. For each simulated individual, residual post-contraception exposure (AUCEOC-∞) was calculated from the end of contraceptive cover to infinity and compared with the predefined safety exposure threshold. The probability of remaining below the threshold was estimated across total contraceptive durations of 1-6 months. Durations were considered supportive of contraceptive discontinuation if ≥50% of the simulated population remained below the safety threshold, in line with the ICH S5 guideline and EFPIA-PDEG consensus.
Results: Systemic exposure at the rat NOAEL corresponded to an AUC₀-∞ of 25 mg/L·day. Applying a 10-fold safety margin yielded a reproductive safety exposure threshold of 2.5 mg/L·day. Despite established PK differences, the required contraception durations did not differ between Eastern African and Indian populations, nor between VL and PKDL patients receiving the same treatment duration. In Eastern African VL patients receiving a 14-day miltefosine regimen, a total contraceptive duration of 3 months resulted in 70.7% of simulated individuals remaining below the safety threshold, whereas 4 months were required for those receiving a 28-day regimen. In Eastern African PKDL, total contraceptive durations of 4 and 5 months were required for the 28- and 42-day regimens, resulting in 67.3% and 90.2% of individuals below the threshold, respectively. For Indian PKDL patients receiving a 21-day regimen, 4 months of contraception resulted in 90.0% remaining below the safety threshold. No systematic differences were observed across age or body-weight strata.
Conclusion: Reproductive safety following miltefosine treatment can be ensured with substantially shorter and more pragmatic contraceptive cover than current recommendations based on the terminal half-life. For the 14-day miltefosine combination regimen used for VL, a 3-month contraception period may be sufficient and could be readily implemented in clinical practice using a single dose of depot medroxyprogesterone acetate administered at treatment initiation.
References:
[1] Sunyoto T, Potet J, Boelaert M. Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most. BMJ Glob Health. 2018;3(3):e000709.
[2] ICH S5 (R3) Guideline on detection of reproductive and developmental toxicity for human pharmaceuticals – Scientific guideline | European Medicines Agency (EMA) [Internet]. 2020 [cited 2026 Jan 15]. Available from: https://www.ema.europa.eu/en/ich-s5-r3-guideline-detection-reproductive-developmental-toxicity-human-pharmaceuticals-scientific-guideline
[3] Bowman CJ, Becourt-Lhote N, Boulifard V, Cordts R, Corriol-Rohou S, Enright B, et al. Science-Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels. Clin Pharmacol Ther. 2023 Feb;113(2):226–45.
[4] Chu WY, Verrest L, Younis BM, Musa AM, Mbui J, Mohammed R, et al. Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa. J Infect Dis. 2024 Dec 16;230(6):e1375–84.
[5] IMPAVIDO (miltefosine) capsules – the Impavido label [Internet]. 2014 [cited 2026 Jan 15]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf
Reference: PAGE 34 (2026) Abstr 12168 [www.page-meeting.org/?abstract=12168]
Poster: Clinical Applications