{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:01:18Z","timestamp":1790654478545,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cutaneous leishmaniasis is a neglected tropical disease with only one oral treatment option. DNDI\u20106148 is an orally bioavailable compound with potent antiparasitic activity in preclinical studies. Establishing skin target\u2010site pharmacokinetic\/pharmacodynamic (PK\/PD) relationships is essential to enable its clinical development. The objective was to characterize the target\u2010site PK and PD of DNDI\u20106148 in a murine\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>L. major<\/jats:italic>\n                    <\/jats:styled-content>\n                    model and to predict a human efficacious dose. A nonlinear mixed\u2010effects PK\/PD model was developed using data from\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>L. major<\/jats:italic>\n                    <\/jats:styled-content>\n                    \u2010infected BALB\/c mice orally administered DNDI\u20106148 (6.25\u201350\u2009mg\/kg, bid). The murine PD components and skin distribution characteristics were used jointly with allometrically scaled human PK parameters to predict a clinically efficacious dose. DNDI\u20106148 PK in mice was described by a one\u2010compartment model with dose\u2010dependent bioavailability, saturable clearance, and a skin\u2010to\u2010plasma ratio of 0.56 [95% CI, 0.49\u20130.68] for both infected and non\u2010infected skin. Parasite clearance at the infection site followed a sigmoidal\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>max<\/jats:italic>\n                    <\/jats:sub>\n                    relationship, driven by free skin concentrations (\n                    <jats:italic>\n                      fEC5\n                      <jats:sub>0<\/jats:sub>\n                    <\/jats:italic>\n                    : 165\u2009\u03bcg\/L [95% CI, 125\u2013236]). Human PK parameters for clearance, volume of distribution, and absorption rate were predicted to 3.44\u2009L\/h, 79.5\u2009L and 0.360\u2009h\n                    <jats:sup>\u22121<\/jats:sup>\n                    , respectively. DNDI\u20106148 doses of 4.0 and 6.0\u2009mg\/kg once daily for 14\u2009days were predicted to achieve 95% and 99% parasite reduction from baseline, respectively, in &gt;\u200990% of simulated patients. This translational PK\/PD modeling framework based on a murine infection model of cutaneous leishmaniasis effectively informs human dose selection by accounting for both PK and PD at the skin target site.\n                  <\/jats:p>","DOI":"10.1111\/cts.70535","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:36:04Z","timestamp":1776166564000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Translational Pharmacokinetic\u2010Pharmacodynamic Modeling and Efficacious Human Dose Prediction of\n                    <scp>DNDI<\/scp>\n                    \u20106148 for the Treatment of Cutaneous Leishmaniasis"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4129-3755","authenticated-orcid":false,"given":"Rasmus Hansen","family":"Henninger","sequence":"first","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wietse M.","family":"Schouten","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology Antoni van Leeuwenhoek\/the Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8407-7093","authenticated-orcid":false,"given":"Byron","family":"Arana","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1467-0403","authenticated-orcid":false,"given":"Jean\u2010Yves","family":"Gillon","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3538-8116","authenticated-orcid":false,"given":"Charles E.","family":"Mowbray","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadel M\u00fcller","family":"Kratz","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative Latin America  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Van Bocxlaer","sequence":"additional","affiliation":[{"name":"Skin Research Centre, Hull York Medical School, York Biomedical Research Institute University of York  York UK"}],"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 Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization Leishmaniasis \u201cleishmaniasis \u201d(2023) https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/leishmaniasis."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000456543"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01437"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2019.02.002"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55474-3"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2024.124377"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"e_1_2_9_10_1","volume-title":"NONMEM Users Guides, NONMEM Project Group","author":"Beal S.","year":"1992"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:JOPA.0000012998.04442.1f"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9112-5"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012299115260"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12161"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9542-0"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1890\/03-0757"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05208-11"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01062336"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(96)00339-6"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127000004001214"},{"key":"e_1_2_9_22_1","volume-title":"Committee for Medicinal Products for Human Use (CHMP) Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antimicrobial medicinal products","author":"European Medicines Agency","year":"2017"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1086\/382135"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab276"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"J.\u2010Y.Gillon R. A.Rijal P.Olliaro et\u00a0al. \u201cSafety Tolerability and Pharmacokinetics of DNDI\u20106148 A Novel Agent for Leishmaniasis: A Randomized Controlled Single Ascending Dose Study in Healthy Participants \u201d(2025) https:\/\/doi.org\/10.22541\/au.174383476.63888393\/v1.","DOI":"10.22541\/au.174383476.63888393\/v1"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2184.1987.tb01355.x"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70535","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70535","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70535","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T04:25:08Z","timestamp":1777955108000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1111\/cts.70535"],"URL":"https:\/\/doi.org\/10.1111\/cts.70535","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2026-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70535"}}