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In order to differentiate the specific contribution of CYP3A from P\u2010gp, the potential interaction with quinidine, a strong inhibitor of P\u2010gp but not CYP3A, was studied as well. Using a fixed\u2010sequence, 3\u2010way crossover design, 20 healthy male subjects received single oral doses of 10\u00a0mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200\u00a0mg itraconazole once daily for 9\u00a0days plus leniolisib on day 5, and (3) 300\u00a0mg quinidine administered 1\u00a0h before and 3\u00a0h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUC<jats:sub>inf<\/jats:sub>) by on average 2.1\u2010fold, whereas the peak drug concentration (C<jats:sub>max<\/jats:sub>) was less impacted (1.25\u2010fold). The terminal elimination half\u2010life (T<jats:sub>1\/2<\/jats:sub>) of leniolisib was also increased by ~2\u2010fold. Neither oral AUC<jats:sub>inf<\/jats:sub>nor C<jats:sub>max<\/jats:sub>or T<jats:sub>1\/2<\/jats:sub>was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our<jats:italic>in vitro<\/jats:italic>findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant<jats:italic>in vivo<\/jats:italic>substrate for intestinal or hepatic P\u2010gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. The concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.<\/jats:p>","DOI":"10.1002\/bdd.2157","type":"journal-article","created":{"date-parts":[[2018,9,1]],"date-time":"2018-09-01T11:37:51Z","timestamp":1535801871000},"page":"394-402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["CYP3A but not P\u2010gp plays a relevant role in the<i>in vivo<\/i>intestinal and hepatic clearance of the delta\u2010specific phosphoinositide\u20103 kinase inhibitor leniolisib"],"prefix":"10.1002","volume":"39","author":[{"given":"Stefan","family":"De Buck","sequence":"first","affiliation":[{"name":"Novartis Pharma AG Novartis Institute for Biomedical Research Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Kucher","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG Novartis Institute for 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