title: Effects of Rifampin, a potent inducer of drug-metabolizing enzymes and an inhibitor of OATP1B1/3 transport, on the single dose pharmacokinetics of anacetrapib.
abstract: Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ 07065, USA. matt.anderson@merck.com
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Daria
authors.initials: D
authors.lastname: Stypinski
authors.forename: Patrice
authors.initials: P
authors.lastname: Auger
authors.forename: Anne
authors.initials: A
authors.lastname: Hohnstein
authors.forename: Scott
authors.initials: S
authors.lastname: Rasmussen
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012293:Rifampin / Q000009:adverse effects / Q000494:pharmacology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D055815:Young Adult
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D023303:Oxazolidinones; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C530884:anacetrapib; D012293:Rifampin