Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin.
OBJECTIVE
Evista (raloxifene HCl) is a nonsteroidal selective estrogen receptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. The potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy postmenopausal women.


METHODS
Single doses of warfarin (20 mg) were administered prior to and during 2 weeks of dosing with raloxifene 120 mg/day. Each warfarin dose was followed by pharmacokinetic sampling and prothrombin time measurements.


RESULTS
Raloxifene administration resulted in 7.1% and 14.1% decreases in the clearance (CLp/F) and 7.4% and 9.8% decreases in the volume of distribution (Vss/F) of R- and S-warfarin, respectively (all p < or = 0.05). In contrast to the slightly higher plasma concentrations of R- and S-warfarin, raloxifene reduced the maximum prothrombin time (PTmax) by 10% and the area under the PT versus time curve from 0-120 h (AUCPT) by 8% (p < 0.01).


CONCLUSIONS
Raloxifene administration may result in a small increase in systemic warfarin exposure that is associated with a diminution, not augmentation, of the pharmacodynamic effect. Due to the small magnitude of this effect, concomitant administration of raloxifene and warfarin is not likely to result in clinically significant drug-drug interaction.
Miller
J W
JW
Eli Lilly & Co, Inc. Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, Indianapolis 46202, USA. jmil@lilly.com
Skerjanec
A
A
Knadler
M P
MP
Ghosh
A
A
Allerheiligen
S R
SR
D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D016001:Confidence Intervals; D004347:Drug Interactions; D004965:Estrogen Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood; D011516:Prothrombin / Q000378:metabolism; D011517:Prothrombin Time; D020849:Raloxifene Hydrochloride / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000925:Anticoagulants; D004965:Estrogen Antagonists; D020849:Raloxifene Hydrochloride; D014859:Warfarin; D011516:Prothrombin