{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:52:04Z","timestamp":1792525924374,"version":"4.5.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004423","name":"World Health Organization","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004423","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009131","name":"Swiss Agency for Development and Cooperation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007729","name":"Dutch Ministry of Foreign Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["91617140"],"award-info":[{"award-number":["91617140"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["2022-01251"],"award-info":[{"award-number":["2022-01251"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20\u2005mg\/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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73\u2005\u00b5g\/g (IQR: 21.94\u201360.65\u2005\u00b5g\/g) in skin and 33.29\u2005\u00b5g\/mL (IQR: 25.9\u201342.58\u2005\u00b5g\/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79\u20131.9). In 87% (45\/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6\u2005mg\/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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkae129","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T13:57:05Z","timestamp":1715349425000},"page":"1547-1554","source":"Crossref","is-referenced-by-count":8,"title":["Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia"],"prefix":"10.1093","volume":"79","author":[{"given":"Semra","family":"Pali\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-8807","authenticated-orcid":false,"given":"Wan-Yu","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital , Amsterdam , The Netherlands"},{"name":"Department of Pharmacy, Uppsala University , Uppsala , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Sundar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Banaras Hindu University , Varanasi , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Mondal","sequence":"additional","affiliation":[{"name":"Centre for Nutrition and Food Security (CNFS), International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) , Dhaka , Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Das","sequence":"additional","affiliation":[{"name":"Rajendra Memorial Research Institute of Medical Sciences (RMRIMS) , Patna , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Pandey","sequence":"additional","affiliation":[{"name":"Rajendra Memorial Research Institute of Medical Sciences (RMRIMS) , Patna , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheeraz","family":"Raja","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative (DNDi) South Asia , New Delhi , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Rijal","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative (DNDi) South Asia , New Delhi , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignace C","family":"Roseboom","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Hamadeh","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Waterloo , Waterloo, Ontario , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R V","family":"Malik","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Waterloo , Waterloo, Ontario , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos H","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital , Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D R","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital , Amsterdam , The Netherlands"},{"name":"Department of Pharmacology, Princess M\u00e1xima Center for Pediatric Oncology , Utrecht , The Netherlands"},{"name":"Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Sj\u00f6gren","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University , Uppsala , Sweden"},{"name":"Pharmetheus AB , Uppsala , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Alves","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative (DNDi) , Geneva , 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