Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia

• Published in: Journal of antimicrobial chemotherapy 2024-07, Vol.79 (7), p.1547-1554
• Main Authors: Palić, Semra, Chu, Wan-Yu, Sundar, Shyam, Mondal, Dinesh, Das, Pradeep, Pandey, Krishna, Raja, Sheeraz, Rijal, Suman, Roseboom, Ignace C, Hamadeh, Abdullah, Malik, Paul R V, Beijnen, Jos H, Huitema, Alwin D R, Sjögren, Erik, Alves, Fabiana, Dorlo, Thomas P C
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amphotericin B - administration & dosage; Amphotericin B - pharmacokinetics; Amphotericin B - therapeutic use; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - pharmacokinetics; Antiprotozoal Agents - therapeutic use; Asia, Southern; Female; Humans; Leishmaniasis, Cutaneous - drug therapy; Leishmaniasis, Cutaneous - parasitology; Leishmaniasis, Visceral - drug therapy; Male; Middle Aged; Original Research; Phosphorylcholine - administration & dosage; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacokinetics; Phosphorylcholine - therapeutic use; Skin - parasitology; Young Adult
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkae129

Abstract Introduction Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. Methods Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20 mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. Results Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 µg/g (IQR: 21.94–60.65 µg/g) in skin and 33.29 µg/mL (IQR: 25.9–42.58 µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79–1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6 mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. Conclusion This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.