The effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol.
OBJECTIVE
The potential for a drug interaction was investigated between nateglinide, an oral antidiabetic agent, and acenocoumarol, an oral anticoagulant, as these drugs are primarily metabolized via CYP2C9.


METHODS
A two-period, randomized, double-blind, two-way crossover study design was employed to evaluate the effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol in 11 healthy male or female subjects. All subjects received either nateglinide 120 mg t.i.d. or placebo for 5 days in a crossover fashion and a single 10-mg dose of acenocoumarol on day 3. Plasma concentrations of R- and S-acenocoumarol and the anticoagulation parameters [prothrombin time (PT) and international normalized ratio of PT (PTINR)] were determined for 72 h following acenocoumarol administration. The pharmacokinetic and pharmacodynamic parameters of acenocoumarol were determined by noncompartmental analysis.


RESULTS
The mean (coefficient of variation (CV%)) area under the concentration-time curve (AUC(0-t)) of R-acenocoumarol in the presence and absence of nateglinide was 4217 (23%) and 3831 (24%) ng.h/ml, respectively. The corresponding values for S-acenocoumarol were 397 (20%) and 382 (23%), respectively. The mean (CV%) C(max) of R-acenocoumarol in the presence and absence of nateglinide was 304 (16%) and 316 (16%), respectively and the corresponding values for S-acenocoumarol were 142 (36%) and 141 (34%), respectively. The 90% confidence intervals indicated that exposure parameters, AUC(0-t) and C(max), of both R- and S-acenocoumarol were within the acceptable limits of 0.8-1.25. The mean (CV%) of area under the concentration-time curve of PT (AUC(PT)) following acenocoumarol administration in the presence and absence of nateglinide was 1170 (10%) and 1136 (8%), respectively. The corresponding AUC(INR) values were 104 (13%) and 99 (10%), respectively. Nateglinide co-administration has no influence on the PT or PTINR of acenocoumarol (p > 0.05).


CONCLUSIONS
Co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are coadministered in clinical practice.
Sunkara
Gangadhar
G
Clinical Pharmacology, Novartis Pharmaceuticals Co., One Health Plaza, East Hanover, NJ 07936-1080, USA.
Bigler
Hilde
H
Wang
Yibin
Y
Smith
Harold
H
Prasad
Pratapa
P
McLeod
James
J
Ligueros-Saylan
Monica
M
D000074:Acenocoumarol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D011517:Prothrombin Time; D012449:Safety
D000925:Anticoagulants; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D010649:Phenylalanine; D000074:Acenocoumarol