Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin.
OBJECTIVE
To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK1)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting.


METHODS
This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10-12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1-3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day -1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily.


RESULTS
The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC(0-24 h) and C(max). However, compared with placebo, trough S(-) warfarin concentrations decreased on days 5-8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011).


CONCLUSIONS
These data are consistent with a significant induction of CYP2C9 metabolism of S(-) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7-10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.
Center for Clinical Pharmacology, U. Z. Gasthuisberg (K. U. Leuven), Herestraat 49, B-3000, Leuven, Belgium, marleen.depre@uz.kuleuven.ac.be
M
M
Depré
A
A
Van Hecken
M
M
Oeyen
I
I
De Lepeleire
T
T
Laethem
P
P
Rothenberg
K J
KJ
Petty
A
A
Majumdar
T
T
Crumley
D
D
Panebianco
A
A
Bergman
J N
JN
de Hoon
D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology*; D000077608:Aprepitant; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004311:Double-Blind Method; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D011517:Prothrombin Time; D013997:Time Factors; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000925:Anticoagulants; D000932:Antiemetics; D009025:Morpholines; D000077608:Aprepitant; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases