title: Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.
abstract: BACKGROUND
  • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.
  
  
  OBJECTIVE
  Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted.
  
  
  METHODS
  In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied.
  
  
  RESULTS
  Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96).
  
  
  CONCLUSIONS
  The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ 07065-0900, USA. rajesh_krishna@merck.com
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Daria
authors.initials: D
authors.lastname: Stypinski
authors.forename: Melissa
authors.initials: M
authors.lastname: Ali
authors.forename: Amit
authors.initials: A
authors.lastname: Garg
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Andrea
authors.initials: A
authors.lastname: Maes
authors.forename: Bruce
authors.initials: B
authors.lastname: Degroot
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Susie
authors.initials: S
authors.lastname: Li
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Connolly
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000494:pharmacology*; D011517:Prothrombin Time; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; D014859:Warfarin; C530884:anacetrapib