Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. AIMAnacetrapib 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. METHODSIn 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. RESULTSAnacetrapib 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 Cmax 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). CONCLUSIONThe 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 whe...

Pharmacokinetics and Pharmacodynamics of Anacetrapib in Black and White Healthy Subjects

“…Anacetrapib does not change midazolam exposure to a relevant degree, indicating that anacetrapib is not a CYP3A inhibitor or inducer . Anacetrapib does not impact exposures of digoxin and warfarin . Anacetrapib caused a slight increase in the AUC of simvastatin and simvastatin acid by 1.3‐fold and 1.36‐fold, respectively; however, this effect was not deemed clinically meaningful .…”

Future of Cholesteryl Ester Transfer Protein (CETP) Inhibitors: A Pharmacological Perspective

“…Anacetrapib drug interactions with simvastatin [59] , digoxin [60] , warfarin [61] , the CYP3A4 substrate midazolam [62] and the CYP3A4 inhibitor ketoconazole [62] were studied. Anacetrapib (150 mg) did not influence midazolam clearance [62] .…”

“…Anacetrapib did not meaningfully affect the exposure to digoxin, a cardiovascular agent, and a known P-glycoprotein substrate [60] . Moreover, anacetrapib did not influence the pharmacokinetics or pharmacodynamics of the anticoagulant agent warfarin that is a CYP2C9 substrate with narrow therapeutic index [61] .…”

Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib

“…Similarly, a study evaluating the pharmacokinetic effects of simvastatin, also a sensitive CYP3A substrate, administered as monotherapy or in combination with anacetrapib, revealed no difference 48. Subsequent to these trials, studies have been performed with digoxin and warfarin 49,50. Digoxin is a substrate of the P-gylcoprotein (Pgp)-mediated transport pathway.…”