title: Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.
abstract: In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
authors.affiliation: Merck Research Laboratories, Mailstop RY34-A500, 126 East Lincoln Avenue, Rahway, NJ 07065-0900, USA. rajesh_krishna@merck.com
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Amit
authors.initials: A
authors.lastname: Garg
authors.forename: Brad
authors.initials: B
authors.lastname: Roadcap
authors.forename: Rita
authors.initials: R
authors.lastname: Chiou
authors.forename: James
authors.initials: J
authors.lastname: Dru
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Tine
authors.initials: T
authors.lastname: Laethem
authors.forename: Regina W
authors.initials: RW
authors.lastname: Wang
authors.forename: Varsha
authors.initials: V
authors.lastname: Didolkar
authors.forename: Eva
authors.initials: E
authors.lastname: Vets
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000494:pharmacology; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D023303:Oxazolidinones; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C530884:anacetrapib; D008874:Midazolam; D007654:Ketoconazole