title: A phase I study evaluating the effect of everolimus on the pharmacokinetics of midazolam in healthy subjects.
abstract: The selective mammalian target of rapamycin (mTOR) inhibitor everolimus has demonstrated competitive inhibition of cytochrome P450 enzyme (CYP) 3A4 in vitro; however, its influence on CYP3A4 activity in humans is unknown. This study examined the influence of everolimus on the pharmacokinetics of midazolam, a sensitive CYP3A4/5 substrate, and its 1-hydroxy metabolite in 25 healthy male subjects. Compared with administration of oral midazolam 4 mg/day alone, coadministration with everolimus 10 mg/day increased the midazolam maximum plasma concentration (C(max)) by 25% and the area under the plasma concentration-time curve (AUC) by 30%. The C(max) and AUC of 1-hydroxymidazolam increased by 20% and 25%, respectively. Concomitant administration of everolimus with midazolam did not change the midazolam metabolic ratio (i.e., the ratio of 1-hydroxymidazolam AUC to midazolam AUC) or the midazolam or 1-hydroxymidazolam terminal half-lives (geometric mean ratios for midazolam + everolimus vs. midazolam alone of 0.96, 1.03, and 1.06, respectively). These results suggest everolimus may affect the bioavailability, but not the systemic clearance, of orally coadministered CYP3A4 substrate drugs.
authors: Novartis Pharmaceuticals Corporation, Florham Park, NJ 07932, USA. shweta.urva@novartis.com
authors: Shweta
authors: S
authors: Urva
authors: Emmanuel
authors: E
authors: Bouillaud
authors: Rosemary
authors: R
authors: Delaney
authors: Annette
authors: A
authors: Jappe
authors: Wing
authors: W
authors: Cheung
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D000068338:Everolimus; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008874:Midazolam / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D007166:Immunosuppressive Agents; D000068338:Everolimus; C040081:1-hydroxymethylmidazolam; D008874:Midazolam; D020123:Sirolimus