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We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006\u2010treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100\u2009mg and multiple ascending doses up to 80\u2009mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20\u2009mg b.i.d. and above. Slow re\u2010distribution from target expressing cells resulted in a long terminal half\u2010life and a long\u2010lasting PD effect in ex\u00a0vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well\u2010tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose\u2010limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil\u2010driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.<\/jats:p>","DOI":"10.1111\/cts.13724","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T05:24:43Z","timestamp":1706937883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["LTA4H inhibitor LYS006: Clinical PK\/PD and safety in a randomized phase I clinical trial"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6505-0349","authenticated-orcid":false,"given":"Christian","family":"Loesche","sequence":"first","affiliation":[{"name":"Translational Medicine Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9078-4535","authenticated-orcid":false,"given":"Damien","family":"Picard","sequence":"additional","affiliation":[{"name":"Translational Medicine Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Van\u00a0Hoorick","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit SGS  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6056-6397","authenticated-orcid":false,"given":"Imelda","family":"Schuhmann","sequence":"additional","affiliation":[{"name":"Biomarker Development Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9248-4086","authenticated-orcid":false,"given":"Petra","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Immunology Disease Area Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4980-067X","authenticated-orcid":false,"given":"Kai","family":"Klein","sequence":"additional","affiliation":[{"name":"PK Sciences Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9445-4447","authenticated-orcid":false,"given":"Carole","family":"Schuhler","sequence":"additional","affiliation":[{"name":"Early Development Analytics, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0467-331X","authenticated-orcid":false,"given":"Gebhard","family":"Thoma","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry Novartis Biomedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1857-9885","authenticated-orcid":false,"given":"Christian","family":"Markert","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry Novartis Biomedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1181-7572","authenticated-orcid":false,"given":"Birk","family":"Poller","sequence":"additional","affiliation":[{"name":"PK Sciences Novartis BioMedical Research, Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5550-2961","authenticated-orcid":false,"given":"Natasa","family":"Zamurovic","sequence":"additional","affiliation":[{"name":"Preclinical Safety Novartis BioMedical Research  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0280-4814","authenticated-orcid":false,"given":"H. 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