title: Lack of effect of brivanib on the pharmacokinetics of midazolam, a CYP3A4 substrate, administered intravenously and orally in healthy participants.
abstract: Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
authors.forename: Shariq
authors.initials: S
authors.lastname: Syed
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Clemens
authors.forename: Deanne
authors.initials: D
authors.lastname: Lathers
authors.forename: Georgia
authors.initials: G
authors.lastname: Kollia
authors.forename: Arindam
authors.initials: A
authors.lastname: Dhar
authors.forename: Ian
authors.initials: I
authors.lastname: Walters
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D050216:Metabolic Detoxication, Phase I; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D010352:Patient Dropouts; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D014227:Triazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D011355:Prodrugs; D014227:Triazines; D005346:Fibroblast Growth Factors; C509922:brivanib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D000409:Alanine; D008874:Midazolam