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Lack of Pharmacokinetic and Pharmacodynamic Interactions Between a Smoking Cessation Therapy, Varenicline, and Warfarin: An In Vivo and In Vitro Study

From the Departments of Clinical Research Operations (Dr Burstein), Medical and Developmental Sciences (Dr Clark), Biostatistics (Dr Willavize), Clinical Pharmacology (Ms Gorman, Dr Faessel), and Pharmacokinetics, Dynamics, and Drug Metabolism (Mr Brayman, Mr Grover, Mr Walsky, Dr Obach), Pfizer Global Research & Development, Groton, Connecticut, and Ann Arbor, Michigan.

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1-week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)- and (S)-warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration-time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)-time curve, were also unaffected by steady-state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.

Key Words: Varenicline • warfarin • coadministration • pharmacokinetics • pharmacodynamics • cytochrome P450

Address for correspondence: Aaron H. Burstein, PharmD, Pfizer Global Research and Development, Groton/New London Labs, Eastern Point Road. MS8260-2505, Groton, CT 06340.

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