{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:48:46Z","timestamp":1792705726740,"version":"4.5.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,3,15]],"date-time":"2012-03-15T00:00:00Z","timestamp":1331769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:sec><jats:title>Study Objective<\/jats:title><jats:p>To investigate potential drug\u2010drug interactions between clobazam and cytochrome P450 (<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>) isoenzyme substrates, inhibitors, and inducers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Two, prospective, open\u2010label, single\u2010center, drug\u2010drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2013<jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Clinical research unit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>Fifty\u2010four healthy adult volunteers were enrolled in the two drug\u2010drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox\u2010Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Intervention<\/jats:title><jats:p>In the first drug\u2010drug interaction study, 36 participants received a single oral dose of clobazam 10\u00a0mg on day 1, followed by either ketoconazole 400\u00a0mg once\/day or omeprazole 40\u00a0mg once\/day on days 17\u201322, with a single dose of clobazam 10\u00a0mg coadministered on day 22, to study the effects of <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4 or <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C19 inhibition, respectively, on clobazam and its active metabolite <jats:italic>N<\/jats:italic>\u2010desmethylclobazam (<jats:italic>N<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">CLB<\/jats:styled-content>). In the second study, 18 participants received a drug cocktail consisting of caffeine 200\u00a0mg, tolbutamide 500\u00a0mg, dextromethorphan 30\u00a0mg, and midazolam 4\u00a0mg on days 1 and 19, and clobazam 40\u00a0mg\/day on days 4\u201319, to study clobazam's effects on <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1A2, <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9, <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2D6, and <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements and Main Results<\/jats:title><jats:p>In the first DDI study, coadministration of ketoconazole (a <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub>) 54% and decreased clobazam's maximum plasma concentration (C<jats:sub>max<\/jats:sub>) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for <jats:italic>N<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">CLB<\/jats:styled-content> to a lesser degree. The <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C19 inhibitor omeprazole increased <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub> and C<jats:sub>max<\/jats:sub> of <jats:italic>N<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">CLB<\/jats:styled-content> by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, <jats:italic>N<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">CLB<\/jats:styled-content> has 3\u20134 times greater exposure than clobazam. In the second DDI study, no clinically significant drug\u2010drug interactions were observed between clobazam 40\u00a0mg and the <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content> probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1\u2010hydroxymidazolam metabolite, however, decreased by 27% and increased 4\u2010fold, respectively. Clobazam increased dextromethorphan (<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2D6) <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub> by 95% and C<jats:sub>max<\/jats:sub> by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4 or <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C19, or inhibit <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C19, had negligible effects on clobazam or <jats:italic>N<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">CLB<\/jats:styled-content>. Clobazam did not affect valproic acid or lamotrigine exposures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest no clinically meaningful drug\u2010drug interactions between clobazam and drugs metabolized by <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4, <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C19, <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1A2, or <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9. Concomitant use of drugs metabolized by <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox\u2010Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/j.1875-9114.2012.01028.x","type":"journal-article","created":{"date-parts":[[2012,9,5]],"date-time":"2012-09-05T03:56:30Z","timestamp":1346817390000},"page":"340-353","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Pharmacokinetic Drug Interactions Between Clobazam and Drugs Metabolized by Cytochrome P450 Isoenzymes"],"prefix":"10.1002","volume":"32","author":[{"given":"Mark","family":"Walzer","sequence":"first","affiliation":[{"name":"Lundbeck LLC Deerfield Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihor","family":"Bekersky","sequence":"additional","affiliation":[{"name":"Lundbeck LLC Deerfield Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Blum","sequence":"additional","affiliation":[{"name":"Buffalo Clinical Research Center LLC Buffalo New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwain","family":"Tolbert","sequence":"additional","affiliation":[{"name":"Lundbeck LLC Deerfield Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,3,15]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"3697","article-title":"Exceptional and unrecognized antiepileptic properties of a commercial anxiolytic: clobazam","volume":"100","author":"Gastaut H","year":"1978","journal-title":"Concours Med"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1979.tb05920.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1979.tb04825.x"},{"key":"e_1_2_7_5_1","first-page":"171","volume-title":"Handbook of epilepsy treatment","author":"Shovron S","year":"2010"},{"key":"e_1_2_7_6_1","first-page":"1531","volume-title":"Epilepsy, a comprehensive textbook","author":"Schmidt D","year":"2008"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199937060-00004"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.32.11.1279"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1979.tb04664.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.430010707"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1987.tb03032.x"},{"key":"e_1_2_7_12_1","volume-title":"Data on file","year":"2010"},{"key":"e_1_2_7_13_1","unstructured":"Food and Drug Administration.Draft guidance for industry: drug interaction studies\u2014study design data analysis and implications for dosing and labeling September 2006. 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