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Pharmacokinetic and Pharmacodynamic Evaluation of Warfarin and Nefazodone Coadministration in Healthy Subjects
Author(s) -
Salazar Daniel E.,
Dockens Randy C.,
Milbrath Rochelle L.,
Raymond Ralph H.,
Fulmor I. Edgar,
Chaikin Philip C.,
Uderman Howard D.
Publication year - 1995
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1995.tb04114.x
Subject(s) - nefazodone , warfarin , pharmacokinetics , pharmacodynamics , pharmacology , placebo , drug interaction , anesthesia , prothrombin time , medicine , serotonin , receptor , alternative medicine , pathology , fluoxetine , atrial fibrillation
Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady‐state warfarin concentrations and a stable prothrombin ratio. Nefazodone 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 events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady‐state pharmacokinetics of R‐warfarin based on within‐subject or comparison to placebo‐treated subjects. The steady‐state AUC TAU over the dosing interval and C max of S‐warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady‐state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well‐tolerated with no clinically significant interactions.