A phase I study evaluating the effect of everolimus on the pharmacokinetics of midazolam in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 53; no. 4; p. 444
• Main Authors: Urva, Shweta, Bouillaud, Emmanuel, Delaney, Rosemary, Jappe, Annette, Cheung, Wing
• Format: Journal Article
• Language: English
• Published: England 01.04.2013
• Subjects: Adult; Anti-Anxiety Agents - adverse effects; Anti-Anxiety Agents - blood; Anti-Anxiety Agents - pharmacokinetics; Drug Interactions; Everolimus; Humans; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - blood; Hypnotics and Sedatives - pharmacokinetics; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Male; Midazolam - adverse effects; Midazolam - analogs & derivatives; Midazolam - blood; Midazolam - pharmacokinetics; Middle Aged; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Young Adult
• ISSN: 1552-4604
• DOI: 10.1002/jcph.7

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.