{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T13:51:50Z","timestamp":1788616310708,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T00:00:00Z","timestamp":1595030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:p>Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug\u2013drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug\u2013drug interaction study. This observation was made in a drug\u2013drug interaction study with the Bruton\u2019s tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (C<jats:sub>max<\/jats:sub>) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (T<jats:sub>max<\/jats:sub>) was observed in the itraconazole group. The <jats:italic>in vitro<\/jats:italic> binding constant between fenebrutinib and hydroxypropyl\u2010<jats:bold>\u03b2<\/jats:bold>\u2010cyclodextrin was determined to be 2\u00a0\u00d7\u00a010<jats:sup>5<\/jats:sup>\u00a0M<jats:sup>\u22121<\/jats:sup>, and the apparent permeability of fenebrutinib across a Madin\u2010Darby canine kidney cell monolayer decreased in a cyclodextrin concentration\u2010dependent manner. This observation was confirmed <jats:italic>in vivo<\/jats:italic>, in a pentagastrin\u2010pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in C<jats:sub>max<\/jats:sub>, a prolonged T<jats:sub>max<\/jats:sub>, and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supported the hypothesis that complexation with cyclodextrin decreased rate and extent of fenebrutinib absorption. Physiologically\u2010based pharmacokinetic modeling was used to translate the <jats:italic>in vitro<\/jats:italic> effect of cyclodextrin on fenebrutinib apparent permeability to the <jats:italic>in vivo<\/jats:italic> effect on absorption, which was then confirmed using the <jats:italic>in vivo<\/jats:italic> dog pharmacokinetic data.<\/jats:p>","DOI":"10.1002\/cpt.1943","type":"journal-article","created":{"date-parts":[[2020,6,14]],"date-time":"2020-06-14T08:54:55Z","timestamp":1592124895000},"page":"1224-1232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Understanding the Effect of Hydroxypropyl\u2010\u03b2\u2010Cyclodextrin on Fenebrutinib Absorption in an Itraconazole\u2013Fenebrutinib Drug\u2013Drug Interaction Study"],"prefix":"10.1111","volume":"108","author":[{"given":"Matthew R.","family":"Durk","sequence":"first","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas S.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Small Molecule Pharmaceutical Sciences Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Nagapudi","sequence":"additional","affiliation":[{"name":"Department of Small Molecule Pharmaceutical Sciences Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Small Molecule Pharmaceutical Sciences Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile G.","family":"Plise","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob Z.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie W.","family":"Chinn","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po\u2010Chang","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Small Molecule Pharmaceutical Sciences Genentech, Inc. South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr970025p"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.562"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01712"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1056"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.8b00688"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1995.tb00001.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-004-1185-3"},{"key":"e_1_2_10_8_1","volume-title":"Pharmacokinetics","author":"Gibaldi M.","year":"1983"},{"key":"e_1_2_10_9_1","unstructured":"European Medicines Agency.Cyclodextrins Used as Excipients European Medical Agencyhttps:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/questions-answers-cyclodextrins-used-excipients-medicinal-products-human-use_en.pdf(October2017)."},{"key":"e_1_2_10_10_1","unstructured":"Reuscher H.GRAS notice for alpha\u2010cyclodextrin wacker chemical corporation. US Food and Drug Administrationhttps:\/\/www.fda.gov\/media\/101653\/download(November2016)."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.53.958"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23077"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2004.07.014"},{"key":"e_1_2_10_14_1","unstructured":"Bextrin Cap MEDPLUSMART<https:\/\/www.medplusmart.com\/product\/BEXTRIN\u2010CAP\/BEXT0002>. Accessed August 7 2019."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118916926"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.2010.01030.x"},{"key":"e_1_2_10_17_1","unstructured":"Backensfeld T. Heil W.&Lipp R.Compositions comprising drospirenone and a complex between ethinyl\u2010estradiol and a cyclodextrin. EP1632237B1. European Patent Office 2001."},{"key":"e_1_2_10_18_1","unstructured":"Center for Drug Evaluation and Research US Food and Drug Administration. Application 21\u2010676 <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2006\/021676s000_CLINPHARMR.pdf> (2004). Accessed August 7 2019."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/000163598422893"},{"key":"e_1_2_10_20_1","unstructured":"Sporanox [package insert] Janssen Pharmaceutica N.V.(2010)."},{"key":"e_1_2_10_21_1","unstructured":"Carlsson T.&Andersson S.Smoking substitute. US5512306A. United States Patent Office 1996. <https:\/\/patentimages.storage.googleapis.com\/ee\/ac\/3b\/6ea67303dc39ad\/US5512306.pdf>. Accessed August 7 2019"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0011-393X(03)00087-0"},{"key":"e_1_2_10_23_1","unstructured":"Kovacic M.&Husu\u2010Kovacevic B.A pharmaceutical composition comprising perindopril. EP1815857A1. European Patent Office 2007."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.2174\/09298673113209990115"},{"key":"e_1_2_10_25_1","unstructured":"Public Assessment Report.Decentralised procedure. Risperidone 1mg\/mL Oral Solution <https:\/\/www.medicines.org.uk\/emc\/files\/pil.3048.pdf>; <https:\/\/www.fda.gov\/drugs\/drug\u2010approvals\u2010and\u2010databases\/inactive\u2010ingredients\u2010database\u2010download>. Accessed August 7 2019."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600840819"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470926819"},{"key":"e_1_2_10_28_1","unstructured":"Cyclodextrin News. February2013 Volume27 No. 2 ISSN 0951\u2010256X."},{"key":"e_1_2_10_29_1","unstructured":"CERSI Center of Excellence in Regulatory Science and Innovation. Excipients Browser <http:\/\/excipients.ucsf.bkslab.org\/index>. Accessed August 7 2019."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcpt.1943","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1943","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.1943","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1943","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:29:08Z","timestamp":1699363748000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.1943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,18]]},"references-count":29,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10.1002\/cpt.1943"],"URL":"https:\/\/doi.org\/10.1002\/cpt.1943","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,18]]},"assertion":[{"value":"2020-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}