PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF WARFARIN AND NEFAZODONE COADMINISTRATION IN HEALTHY-SUBJECTS

Nefazodone, an antidepressant with serotonin and norepinephrine recept or modulating activity, is highly protein bound and eliminated by oxid ative metabolism. This study evaluated the potential for clinically si gnificant drug interactions with warfarin and nefazodone coadministrat ion. Eighteen subjects received warfarin daily for 14 days, achieving steady-state warfarin concentrations and a stable prothrombin ratio. N efazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double-blind, randomized design. No serious or unexpected adverse ev ents or events suggestive of abnormal bleeding occurred during coadmin istration. The addition of nefazodone had no effect on the unbound fra ction of total warfarin in plasma or on the steady-state pharmacokinet ics of R-warfarin based on within-subject or comparison to placebo-tre ated subjects. The steady-state AUC(TAU) over the dosing interval and C-max of S-warfarin decreased by 12%; however, this change is clinical ly insignificant because the prothrombin ratio and bleeding time remai ned unchanged. The steady-state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of h ealthy men treated with this nefazodone dosage. In conclusion, warfari n and nefazodone coadministration was safe and well-tolerated with no clinically significant interactions.