Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.
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.
Krishna
Rajesh
R
Merck Research Laboratories, Mailstop RY34-A500, 126 East Lincoln Avenue, Rahway, NJ 07065-0900, USA. rajesh_krishna@merck.com
Bergman
Arthur J
AJ
Jin
Bo
B
Garg
Amit
A
Roadcap
Brad
B
Chiou
Rita
R
Dru
James
J
Cote
Josee
J
Laethem
Tine
T
Wang
Regina W
RW
Didolkar
Varsha
V
Vets
Eva
E
Gottesdiener
Keith
K
Wagner
John A
JA
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
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