Abstract
Background
Fimasartan is an angiotensin II receptor antagonist used to treat hypertension.
Objective
The aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics
and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements
for drug marketing and labeling in Korea.
Methods
An open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in
healthy male volunteers. The subjects were administered a single-dose of warfarin
25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered
every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly
with fimasartan. Serial blood samples were collected for 144 hours after each warfarin
dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS,
and the pharmacokinetic parameters were estimated by using noncompartmental analysis.
The maximal international normalized ratio (INR) and the AUC–INR curve were evaluated
to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements,
physical examinations, ECGs, clinical laboratory tests, and adverse events.
Results
A total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years)
and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed
the study. The geometric mean ratios (GMRs [90% CIs]) of Cmax and AUC0–last for R-warfarin were 1.06 (0.97–1.16) and 1.07 (1.03–1.12), respectively. For S-warfarin,
the GMRs (90% CIs) of Cmax and AUC0–last were 1.02 (0.94–1.11) and 0.99 (0.94–1.04). The INR values reached 1.93 (0.31) and
1.96 (0.37) at 36 hours and decreased to <1.2 at 144 hours after warfarin treatment
alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the
maximal INR and AUC–INR curve were 1.01 (0.97–1.05) and 0.98 (0.96–1.01). One (7.7%)
of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2
(16.7%) of 12 subjects receiving the combination treatment experienced headache, skin
erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated
INR >4 or reported any symptoms related to hypotension, including fainting or dizziness.
Conclusion
Multiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics
of warfarin in this small, select population of healthy male volunteers. ClinicalTrials.gov identifier: NCT00923533.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects.Am J Cardiovasc Drugs. 2011; 11: 335-346
- Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, Phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.Clin Ther. 2012; 34: 552-568
- Angiotensin II receptor blockers.Proc (Bayl Univ Med Cent). 2003; 16: 123-126
- Fimasartan.Am J Cardiovasc Drugs. 2011; 11: 249-252
- The effect of the newly developed angiotensin receptor II antagonist fimasartan on the pharmacokinetics of atorvastatin in relation to OATP1B1 in healthy male volunteers.J Cardiovasc Pharmacol. 2011; 58: 492-499
- Increased systemic exposure of fimasartan, an angiotensin II receptor antagonist, by ketoconazole and rifampicin.J Clin Pharmacol. 2012 Jan 26; ([Epub ahead of print])
- Pharmacokinetic interaction of fimasartan, a new angiotensin II receptor antagonist, with amlodipine in healthy volunteers.J Cardiovasc Pharmacol. 2011; 57: 682-689
- Assessment of the drug-drug interactions between fimasartan and hydrochlorothiazide in healthy volunteers.J Cardiovasc Pharmacol. 2012; 59: 84-91
- Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers.Int J Clin Pharmacol Ther. 2011; 49: 321-327
- Warfarin—indications, risks and drug interactions.Aust Fam Physician. 2010; 39: 476-479
- The international normalized ratio.Arch Intern Med. 1994; 154: 282-288
- Warfarin and its interactions with foods, herbs and other dietary supplements.Expert Opin Drug Saf. 2006; 5: 433-451
- Systematic overview of warfarin and its drug and food interactions.Arch Intern Med. 2005; 165: 1095-1106
- Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, 55th WMA General Assembly, Tokyo 2004.(Accessed June 20, 2011)
- Guideline for Good Clinical Practice E6 (R1) Step 4 version, ICH Harmonised Tripartite Guideline, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.(Accessed June 20, 2011)
- Comparative consistency between obesity determination standards using body mass index and ideal body weight.J Korean Acad Fam Med. 2001; 22: 1765-1771
- Supercritical fluid chromatography-tandem mass spectrometry for fast bioanalysis of R/S-warfarin in human plasma.J Pharm Biomed Anal. 2006; 42: 573-580
- Validation of a method for the determination of (R)-warfarin and (S)-warfarin in human plasma using LC with UV detection.J Pharm Biomed Anal. 2000; 22: 573-581
- Pharmacokinetic and Pharmacodynamic Data Analysis, Concepts and Applications.4th ed. CRC Press, Boca Raton, Fla2007
- 33rd Report, WHO Technical Report Series 687.in: WHO, Geneva1983: 81-105 (Accessed June 20, 2011)
- International collaborative study for the calibration of a proposed reference preparation for thromboplastin, human recombinant, plain.Thromb Haemost. 1998; 79: 439-443
- Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.Eur J Clin Pharmacol. 2008; 64: 961-966
- Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men.J Clin Pharmacol. 2006; 46: 1179-1187
- American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.Circulation. 2003; 107: 1692-1711
- Pharmacokinetics in Drug Development.AAPS Press, Arlington, VA2004
- Absence of a pharmacokinetic interaction between etanercept and warfarin.J Clin Pharmacol. 2004; 44: 543-550
- Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.Br J Clin Pharmacol. 2005; 59: 425-432
- Evaluation of a potential tigecycline-warfarin drug interaction.Pharmacotherapy. 2008; 28: 895-905
- Science snippets.J Am Pharm Assoc (2003). 2010; 50: 552
- Antithrombotic Therapy in Atrial Fibrillation: Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008; 133: 546S-592S
- Pharmacodynamic evaluation of warfarin and rosuvastatin co-administration in healthy subjects.Eur J Clin Pharmacol. 2005; 61: 621-625
- Effect of the catechol-O-methyltransferase inhibitor entacapone on the steady-state pharmacokinetics and pharmacodynamics of warfarin.Br J Clin Pharmacol. 2002; 53: 485-491
- Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin.Pharm Res. 2001; 18: 1024-1028
- Effect of age on the pharmacokinetics of fimasartan (BR-A-657).Expert Opin Drug Metab Toxicol. 2011; 7: 1337-1344
Article info
Publication history
Published online: June 25, 2012
Accepted:
June 5,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
