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. 2026 Mar;67(3):107713.
doi: 10.1016/j.ijantimicag.2026.107713. Epub 2026 Jan 9.

Skin pharmacokinetics and pharmacodynamics in patients with post-kala-azar dermal leishmaniasis

Wan-Yu Chu  1 , Om Prakash Singh  2 , Shyam Sundar  3 , Krishna Pandey  4 , Pradeep Das  5 , Dinesh Mondal  6 , Brima Musa Younis  7 , Ahmed Mudawi Musa  7 , Abhishek Kumar Singh  8 , Deepak Kumar Verma  9 , Rahul Chaubey  9 , Poonam Kumari  9 , Jaya Chakravarty  8 , Major Madhukar  4 , Roshan Kamal Topno  4 , Ashish Kumar  4 , Vinod Kumar  4 , Md Utba Rashid  6 , Shomik Maruf  6 , Prakash Ghosh  6 , Mohammed Abdelrahim Saeed  7 , Eltahir Awad Gasim Khalil  7 , Anas Elbashir Ahmed  7 , Mujahid Ahmed Ali  7 , Ali Noureldin  7 , Ignace C Roseboom  10 , Javier Moreno  11 , Carmen Sanchez  11 , Lorena Bernardo  11 , Jose Solana  11 , Ana Torres  11 , Sheeraz Raja  12 , Joelle Rode  13 , Eugenia Carrillo  11 , Fabiana Alves  14 , Thomas P C Dorlo  15
Affiliations
Free article

Skin pharmacokinetics and pharmacodynamics in patients with post-kala-azar dermal leishmaniasis

Wan-Yu Chu et al. Int J Antimicrob Agents. 2026 Mar.
Free article

Abstract

Background: Treatment regimens and clinical outcomes for post-kala-azar dermal leishmaniasis (PKDL) vary across South Asia and Eastern Africa. We evaluated the skin target site pharmacokinetics (PK) of miltefosine, liposomal amphotericin B (LAmB) and paromomycin and associated pharmacodynamics (PD) on skin parasite reduction and lesion healing, to determine PK/PD factors driving regional differences in clinical outcomes.

Methods: In South Asia, participants (n = 126) received LAmB alone or with miltefosine. In Eastern Africa, participants (n = 110) received LAmB or paromomycin with miltefosine. Skin drug concentrations were compared to the in vitro EC50 of Leishmania donovani to assess PK target attainment, then correlated with skin parasite load and lesion score to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships.

Results: Antileishmanial drug distribution varied in skin. Miltefosine showed the highest skin-to-plasma ratio, with medians of 1.19 (IQR: 0.78-1.88) in South Asia vs. 1.58 (1.1-2.08) in Eastern Africa (P < 0.05). Combining paromomycin or LAmB with miltefosine improved PK target attainment and reduced variability. In South Asia, macular or mixed (macular and papular/nodular) lesions predominated (93%) and were associated with ≥6-fold higher baseline parasite load and lesion score versus Eastern Africa, where papular and maculopapular lesions were more common (97%). By treatment end, parasite loads dropped ≥99% in both regions, with ≤7% above the transmission threshold. Lesion scores decreased by 11% in South Asia and 93% in Eastern Africa.

Conclusions: Similar skin PK target attainment and relative parasite reduction were achieved for all regimens. Regional differences in parasite load and lesion score at baseline and lesion healing rates, suggest disease presentation is the primary factor affecting clinical outcomes.

Keywords: Liposomal amphotericin B; Miltefosine; Paromomycin; Pharmacodynamics; Post-kala-azar dermal leishmaniasis; Skin pharmacokinetics.

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