{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T21:21:10Z","timestamp":1780435270470,"version":"3.54.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T00:00:00Z","timestamp":1597104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Union Seventh Framework Programme (FP7) Africoleish","award":["305178"],"award-info":[{"award-number":["305178"]}]},{"name":"WHO\u2014Special Programme for Research and Training in Tropical Diseases"},{"DOI":"10.13039\/501100011061","name":"French Development Agency","doi-asserted-by":"crossref","award":["CZZ2062"],"award-info":[{"award-number":["CZZ2062"]}],"id":[{"id":"10.13039\/501100011061","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medicor Foundation Liechtenstein"},{"DOI":"10.13039\/100009131","name":"Swiss Agency for Development and Cooperation","doi-asserted-by":"crossref","award":["81017718"],"award-info":[{"award-number":["81017718"]}],"id":[{"id":"10.13039\/100009131","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007729","name":"Dutch Ministry of Foreign Affairs","doi-asserted-by":"crossref","award":["PDP15CH21"],"award-info":[{"award-number":["PDP15CH21"]}],"id":[{"id":"10.13039\/501100007729","id-type":"DOI","asserted-by":"crossref"}]},{"name":"French Ministry for Europe and Foreign Affairs"},{"DOI":"10.13039\/501100004892","name":"Spanish Agency for International Development Cooperation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004892","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ZonMw\/Dutch Research Council","award":["91617140"],"award-info":[{"award-number":["91617140"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Conventional miltefosine dosing (2.5\u2009mg\/kg\/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2\u2009mg\/kg\/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Fifty-one children with VL were included in this analysis, treated with either a conventional (n\u2009=\u200921) or allometric (n\u2009=\u200930) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg\/kg\/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaa314","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T14:07:56Z","timestamp":1593180476000},"page":"3260-3268","source":"Crossref","is-referenced-by-count":17,"title":["Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa"],"prefix":"10.1093","volume":"75","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"}]},{"given":"Anke E","family":"Kip","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":"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":"Jane","family":"Mbui","sequence":"additional","affiliation":[{"name":"Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Musa","sequence":"additional","affiliation":[{"name":"Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Solomos","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Wasunna","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases\u2009initiative, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Olobo","sequence":"additional","affiliation":[{"name":"Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Alves","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-8435","authenticated-orcid":false,"given":"Thomas P C","family":"Dorlo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute\u2014Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,8,11]]},"reference":[{"key":"2020101604551894400_dkaa314-B1","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"2020101604551894400_dkaa314-B2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/j.1365-3156.2009.02279.x","article-title":"The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India","volume":"14","author":"Boelaert","year":"2009","journal-title":"Trop Med Int Heal"},{"key":"2020101604551894400_dkaa314-B3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.2174\/092986709787458489","article-title":"Leishmaniasis: current treatment and prospects for new drugs and 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kidneys","volume":"37","author":"Bianciardi","year":"2009","journal-title":"Toxicol Pathol"},{"key":"2020101604551894400_dkaa314-B7","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1128\/AAC.00014-08","article-title":"Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients","volume":"52","author":"Dorlo","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"2020101604551894400_dkaa314-B8","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1007\/s11095-006-9170-7","article-title":"Intestinal absorption of miltefosine: contribution of passive paracellular transport","volume":"24","author":"M\u00e9nez","year":"2007","journal-title":"Pharm Res"},{"key":"2020101604551894400_dkaa314-B9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s11745-007-3026-8","article-title":"Inward translocation of the phospholipid analogue miltefosine across Caco-2 cell membranes exhibits characteristics of a carrier-mediated 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