Andrés Mazariegos Herrera 1, Mats O. Karlsson 1, Elin M. Svensson 1,2, Thomas P.C. Dorlo 1
1 Deparment of Pharmacy, Uppsala University (Uppsala, Sweden), 2 Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center (Nijmegen, The Netherlands)
Objectives:
Miltefosine is the only oral treatment for all clinical forms of leishmaniasis, ranging from self-healing cutaneous leishmaniasis (CL) to life-threatening visceral leishmaniasis (VL). VL that is inadequately treated may progress to post-kala-azar dermal leishmaniasis (PKDL) (1). Previous pharmacokinetic (PK) studies have reported disease form- and geography-related differences in miltefosine exposure, including lower exposure in Eastern African compared to South Asian PKDL patients (2), lower exposure in VL patients compared to PKDL within the same region (3), and reduced bioavailability during the first week of VL treatment (4). However, these findings have not been evaluated within a global pooled analysis.
This study characterized the population PK of miltefosine across leishmaniasis clinical forms using a single integrated model, aiming to quantify the impact of disease phenotype, geography, and other covariates on drug exposure.
Methods:
A two-stage individual patient data meta-analysis was conducted (5). First, a systematic review identified clinical studies of miltefosine in CL, VL, and PKDL using publicly available sources. Individual participant-level datasets were obtained from all eligible studies and ranked according to data richness at treatment initiation and end of treatment, availability of relevant covariates, anthropometric indicators of disease severity, recency, and presence of concomitant treatments or comorbidities (6).
In the second stage, studies were incorporated stepwise, starting from a base structural model (7). Alternative structural model components were evaluated and retained based on improvements in model performance assessed through goodness-of-fit diagnostics and visual predictive checks. Structural and stochastic components were iteratively re-evaluated as additional data were incorporated. This procedure was repeated until all studies were included. Covariate model building followed a stepwise procedure (6) evaluating geographic region, disease phenotype, nutritional status, and growth-related covariates.
Model-based exposure over 28 days (AUC₀–₂₈d) was simulated for a typical adult across all clinical forms and geographic regions.
Results:
Eleven studies comprising 822 individuals were included (82 CL, 251 PKDL, 489 VL), and model building began with the top-ranked study of adult Dutch CL patients (n=31). Studies covered Colombian CL, Eastern African VL and PKDL, and South Asian VL and PKDL patients with treatment durations ranging from 10–84 days. Some study arms involved combination therapy with paromomycin and liposomal amphotericin B (LAmB).
Miltefosine PK was best described by a two-compartment model with five transit compartments capturing delayed first-order absorption (mean transit time 3.97h) and elimination (initial half-life 6.70 days). Central and peripheral disposition parameters were allometrically scaled using body weight. A cumulative dose-per-kg effect on bioavailability was identified, resulting in a reduction over time, consistent across studies; for a 50-kg individual receiving 100 mg/day, bioavailability would be approximately 50% by the end of a 28-day treatment course.
Significant group differences in bioavailability were identified. CL patients had the highest relative bioavailability. PKDL and VL patients from Eastern Africa had a 15.5% lower relative bioavailability than those from South Asia. Concomitant LAmB reduced F by 7.40%.
In VL, bioavailability at treatment initiation was markedly reduced (F=0.089) with substantial inter-individual variability (121% CV). Bioavailability increased over time following a sigmoidal function linked to parasite clearance, driven by the typical miltefosine-related reduction in VL blood parasite burden, as described by Verrest et al (8), with a time to 50% parasite reduction (TP₅₀) of 4.75 days. In patients receiving concomitant LAmB, parasite clearance was faster (TP₅₀ 0.962 days), leading to earlier recovery of bioavailability despite the direct negative effect of LAmB on bioavailability.
For a typical 50-kg adult receiving 100 mg once daily, simulated AUC₀–₂₈d was lowest in Eastern African VL (603 μg·day/mL) compared to CL (1014 μg·day/mL). In a PKDL patient co-treated with LAmB for 15 days, AUC₀–₂₈d was 938 μg·day/mL, indicating a lower exposure than a CL patient.
Conclusions:
A unified population PK model integrating global miltefosine data identified disease phenotype (VL), geographic region (Eastern Africa), cumulative dose, and coadministration of LAmB as significant determinants of exposure. Reduced bioavailability at treatment initiation in VL could be linked to parasite burden dynamics and recovered with treatment response. Despite these group differences, the cumulative dose effect and absorption transit structure were consistent across all datasets and populations.
This integrated framework quantitatively explains previously reported exposure differences and provides a basis for exposure-response evaluation and dose optimization across leishmaniasis clinical forms.
References:
1. Dorlo TPC, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012 Nov 1;67(11):2576–97. doi:10.1093/jac/dks275
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3. 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 15;230(6):e1375–84. doi:10.1093/infdis/jiae413
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7. Dorlo TPC, van Thiel PPAM, Huitema ADR, Keizer RJ, de Vries HJC, Beijnen JH, et al. Pharmacokinetics of Miltefosine in Old World Cutaneous Leishmaniasis Patients. Antimicrob Agents Chemother. 2008 Aug;52(8):2855–60. doi:10.1128/aac.00014-08
8. Verrest L, Monnerat S, Musa AM, Mbui J, Khalil EAG, Olobo J, et al. Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model. PLOS Neglected Tropical Diseases. 2024 abr;18(4):e0012078. doi:10.1371/journal.pntd.0012078
Reference: PAGE 34 (2026) Abstr 11853 [www.page-meeting.org/?abstract=11853]
Poster: Drug/Disease Modelling - Infection