title: Effect of R667, a novel emphysema agent, on the pharmacokinetics of midazolam in healthy men.
abstract: The purpose of this study was to investigate the potential for a CYP3A4-mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15-mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (C(max) = 50.8 vs 46.2 ng/mL; AUC(0-last) = 215 vs 216 ng.h/mL; AUC(0-last) ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.
authors.affiliation: Hoffmann-La Roche, Nutley, New Jersey, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Angus B
authors.initials: AB
authors.lastname: Brown
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Kolis
authors.forename: Olga
authors.initials: O
authors.lastname: Rutman
authors.forename: Calvin
authors.initials: C
authors.lastname: Gooden
authors.forename: Brian E
authors.initials: BE
authors.lastname: Davies
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004646:Emphysema / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D006993:Hypnotics and Sedatives; D011720:Pyrazoles; C511499:R667 compound; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam