Abstract
Background
Fimasartan is a selective angiotensin II receptor blocker developed for once-daily
dosing.
Objectives
To meet the regulatory requirements for approval of an antihypertensive treatment
in Korea, this pair of studies was conducted to evaluate the efficacy and tolerability
of fimasartan, to determine its dose-response relationship and minimum effective dose,
and to characterize its blood pressure (BP)-reduction profile over the dosing interval.
Methods
These 2 Phase II, randomized, double-blind, placebo-controlled, parallel-group, and
dose-response studies enrolled male or nonchildbearing female Korean patients aged
18 to 65 years (study 1) or 18 to 70 years (study 2) with essential hypertension (sitting
diastolic BP [DBP] 95–<115 mm Hg [study 1] or 90–<110 mm Hg [study 2]). Patients were
randomly assigned to receive fimasartan 20, 60, 120, or 180 mg (study 1) or 20, 60,
120, or 240 mg (study 2) or placebo in the same ratio, once daily for 4 weeks (study
1) or 8 weeks (study 2). Clinic BP was measured at trough, and change from baseline
in DBP at week 4 (study 1) or 8 (study 2) was the primary efficacy end point. In study
1, 24-hour ambulatory BP monitoring (ABPM) was conducted. Treatment-emergent adverse
events (TEAEs) were assessed using a structured questionnaire, laboratory testing,
physical examination, and ECG readings.
Results
Totals of 61 and 195 patients participated in studies 1 and 2, respectively (68% male;
mean age, 50.1 and 55.1 years; DBP, 98.7 and 103.6 mm Hg; systolic BP, 147.0 and 158.1
mm Hg), of whom 52 (85.2%) and 169 (86.7%) completed each study. Data from ABPM were
obtained from 45 patients (73.8%), and safety profile was evaluated in 225 participants.
Four-week treatment with fimasartan 180 mg once daily was associated with a significantly
greater mean reduction in DBP compared with placebo in study 1 (−16.4 vs −5.5 mm Hg;
P = 0.022). In study 2, fimasartan 60, 120, and 240 mg once daily were associated with
significantly greater reductions in DBP after 8 weeks of treatment compared with placebo
(−14.4, −14.1, and −12.7 vs −5.8 mm Hg, respectively; P < 0.0001–< 0.005). Fimasartan 60 mg once daily was the minimum effective dose, and
the dose-response relationship was flat at doses >60 mg once daily. BP reduction was
maintained over the full 24-hour dosing interval (trough-to-peak ratios: 0.41–0.98).
The proportions of patients who experienced TEAEs were comparable among the treatment
groups in both studies, with headache (9.8%) and dizziness (4.4%) being most commonly
reported. No serious AEs were reported.
Conclusions
Once-daily oral administration of fimasartan was well tolerated and efficacious in
reducing BP in these hypertensive Korean patient populations. ClinicalTrials.gov identifiers: NCT00937651 and NCT00923611.
Key words
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References
- Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT(1)) antagonists.Bioorg Med Chem Lett. 2012; 22: 1649-1654
- Fimasartan.Am J Cardiovasc Drugs. 2011; 11: 249-252
- 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
- Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients.Hypertension. 1995; 25: 37-46
- Valsartan: Preclinical and clinical profile of an antihypertensive angiotensin-II antagonist.Cardiovascular Drug Reviews. 1995; 13: 230-250
- Angiotensin II type 1 receptor blockers.Circulation. 2001; 103: 904-912
- Angiotensin II-receptor blockers: will they replace angiotensin-converting enzyme inhibitors in the treatment of hypertension?.J Hum Hypertens. 2000; 14: S87-S90
- Angiotensin receptor blockers: pharmacology, efficacy, and safety.J Clin Hypertens (Greenwich). 2011; 13: 677-686
- Clinical Trial Guidance for Antihypertensive Agents.Korea Food and Drug Administration, Seoul, Korea2009
- 1983 metropolitan height and weight tables.Stat Bull Metrop Life Found. 1983; 64: 3-9
- Korean Good Clinical Practices Guideline.in: Korea Food and Drug Administration, Seoul, Korea2008
- Pharmaceutical Affairs Law. 9123.in: Ministry of Health and Welfare, Seoul, Korea2008
- Lisinopril versus enalapril: evaluation of trough:peak ratio by ambulatory blood pressure monitoring.J Hum Hypertens. 1999; 13: 405-412
- Determining the trough-to-peak ratio in parallel-group trials.Hypertension. 1997; 29: 659-667
- The trough-to-peak ratio as an instrument to evaluate antihypertensive drugs.Hypertension. 1995; 26: 942-949
- Designing clinical trials for two-sided multiple comparisons with a control.Control Clin Trials. 1989; 10: 142-152
- Chow S.C. Shao J. Wang J.S. Sample Size Calculations in Clinical Research. 2nd ed. John Wiley & Sons, New York2003
- Candesartan cilexetil.Drugs. 1998; 56: 847-869
- Clinical efficacy of eprosartan.Pharmacotherapy. 1999; 19: 95S-101S
- Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension.J Hum Hypertens. 2000; 14: S73-S86
- Clinical overview of irbesartan: a new angiotensin II receptor antagonist.Am J Hypertens. 1997; 10: 318S-324S
- Irbesartan.Drugs. 1997; 54: 885-902
- Global efficacy and tolerability of losartan, an angiotensin II subtype 1-receptor antagonist, in the treatment of hypertension.Blood Press Suppl. 1996; 2: 82-86
- Eprosartan.Drugs. 1998; 55: 713-718
- Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists.Pharmacotherapy. 2000; 20: 130-139
- A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension.Hypertension. 1995; 25: 1345-1350
- Comparative antihypertensive effects of losartan 50 mg and losartan 50 mg titrated to 100 mg in patients with essential hypertension.Blood Press. 1997; 6: 35-43
- Once-daily telmisartan compared with enalapril in the treatment of hypertension.Adv Therap. 1998; 15: 229-240
- Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor?.Hypertension. 2003; 41: 31-36
- Dose-response characteristics of olmesartan medoxomil and other angiotensin receptor antagonists.Am J Cardiovasc Drugs. 2007; 7: 347-356
- Some problems with antihypertensive drug studies in the context of the new guidelines.Am J Hypertens. 1990; 3: 151-155
- Draft Guidance: E12A Principles for Clinical Evaluation of New Antihypertensive Drugs.(Accessed February 2012)
- Points to consider on missing data.in: European Agency for the Evaluation of Medicinal Products, London, UK2001
- Missing data and the trouble with LOCF.Evid Based Ment Health. 2008; 11: 3-5
- Does analysis using “last observation carried forward” introduce bias in dementia research?.CMAJ. 2008; 179: 751-753
- Ethnic differences in cardiovascular drug response: potential contribution of pharmacogenetics.Circulation. 2008; 118: 1383-1393
Article info
Publication history
Published online: May 21, 2012
Accepted:
April 20,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
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- CorrectionClinical TherapeuticsVol. 34Issue 9
- PreviewIn the article by H. Lee and colleagues, titled “Efficacy and Tolerability of Once-Daily Oral Fimasartan 20 to 240 mg/d in Korean Patients with Hypertension: Findings from Two Phase II, Randomized, Double-Blind, Placebo-Controlled Studies” (Clin Ther. 2012;34: 1273–1289), sentences in the Acknowledgements section read “All authors contributed equally to the literature search, data interpretation, figure creation, and writing of the manuscript.” The section should have read “All authors contributed extensively to the work presented in this paper.
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