Bioequivalence and Pharmacokinetic Evaluation of Two Tablet Formulations of Carvedilol 25-mg: A Single-Dose, Randomized-Sequence, Open-Label, Two-Way Crossover Study in Healthy Chinese Male Volunteers

Y. Liu; C. Lu; Q. Chen; W. Wang; G.-y. Liu; X.-p. Lu; M.-q. Zhang; C. Yu; J.-y. Jia

doi:10.1055/s-0032-1331768

Drug Research, Table of Contents

Drug Res (Stuttg) 2013; 63(02): 74-78
DOI: 10.1055/s-0032-1331768

Original Article

Bioequivalence and Pharmacokinetic Evaluation of Two Tablet Formulations of Carvedilol 25-mg: A Single-Dose, Randomized-Sequence, Open-Label, Two-Way Crossover Study in Healthy Chinese Male Volunteers

Authors

Y. Liu

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
C. Lu

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
Q. Chen

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
W. Wang

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
G.-y. Liu

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
X.-p. Lu

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
M.-q. Zhang

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
C. Yu

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
J.-y. Jia

¹Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China

Abstract

Background:

Carvedilol is a nonselective-blocking agent and is used in the treatment of hypertension and angina pectoris.

Objective:

The aim of this study was to evaluate bioequivalence of two 25-mg tablet formulations of carvedilol following single oral dose in adult male volunteers.

Methods:

This was a randomized, single-dose, open-label, crossover bioequivalence study. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 h after dosing. Plasma concentrations of Carvedilol were determined by using a validated LC-MS/MS method. Statistical analysis of the pharmacokinetic parameters C_max, AUC_0–24, and AUC_0–∞ was conducted to determine bioequivalence.

Results:

23 healthy male Chinese volunteers were enrolled in the study. The mean (SD) C_max, AUC_0–24, and AUC_0–∞ values after administration of the test and reference formulations, respectively, were as follows: 73.71 (34.04) vs. 78.93 (43.64) ng/mL, 285.1 (147.0) vs. 296.9 (176.1) ng/mL · h, and 296.5 (161.4) vs. 303.4 (177.9) ng/mL · h. The 90% CIs of the ratios (test vs. reference) for the ln-transformed C_max, AUC_0–24, and AUC_{0 − ∞} were 85.3% to 114.3%, 90.4% to 107.6%, and 90.9% to108.4%, respectively, meeting the criteria of SFDA, FDA and EMEA for bioequivalence. The relative bioavailability of the test formulation to reference formulation was 100.1%. Both formulations were generally well tolerated and no serious AEs were reported in the study.

Conclusions:

The 90% CIs for the ratios of mean C_max, AUC_0–24, and AUC_0–∞ met the regulatory criteria for bioequivalence.

Key words

carvedilol - bioequivalence - pharmacokinetics - liquid chromatography tandem mass spectrometry - LC-MS/MS

Full Text

References

References
1 Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349-1355
2 Abshagen U. A new molecule with vasodilating and beta-adrenoceptor blocking properties. J Cardiovasc Pharmacol 1987; 10 (Suppl. 11) S23-S32
3 Ruffolo Jr RR, Gellai M, Hieble JP et al. The pharmacology of carvedilol. Eur J Clin Pharmacol 1990; 38 (Suppl. 02) S82-S88
4 Ong HT, Ong LM, Kow FP. Beta-blockers for heart failure: an evidence based review answering practical therapeutic questions. Med J Malaysia 2012; 67: 7-11 Review
5 Bozkurt B, Bolos M, Deswal A et al. New insights into mechanisms of action of carvedilol treatment in chronic heart failure patients – a matter of time for contractility. J Card Fail 2012; 18: 183-193
6 Fahlbusch SA, Tsikas D, Mehls C et al. Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers. Eur J Clin Pharmacol 2004; 60: 83-88
7 Keating GM, Jarvis B. Carvedilol: a review of its use in chronic heart failure. Drugs 2003; 63: 1697-1741
8 Sehrt D, Meineke I, Tzvetkov M et al. Carvedilol pharmacokinetics and pharmacodynamics in relation to CYP2D6 and ADRB pharmacogenetics. Pharmacogenomics 2011; 12: 783-795
9 World Medical Association Declaration Of Helsinki (WMA) Ethical Principles for Medical Research Involving Human Subjects. Adopted by the 18^th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 52^nd WMA General Assembly, Edinburgh, Scotland, October 7, 2000 http://www.wma.net/en/30publications/10policies/b3/index.html Accessed September 20, 2007
10 European Agency for the Evaluation of Medicinal Products (EMA). International Conference on Harmonisation – World Health Organization. Guideline for Good Clinical Practice. ICH topic E 6 (R1) http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf
11 State Food and Drug Administration. Guideline for Good Clinical Practice [in Chinese]. http://www.sda.gov.cn/WS01/CL0053/24473.html Accessed December 1, 2009
12 Shumaker RC. PKCALC: A BASIC interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev 1986; 17: 331-348
13 State Food and Drug Administration, Center for Drug Evaluation. Guideline for bioavailability and bioequivalence studies of generic drug products [in Chinese]. http://www.cde.org.cn/zdyz.do?method=largePage&id=2066 Accessed December 01, 2009
14 Portolés A, Filipe A, Almeida S et al. Bioequivalence study of two different tablet formulations of carvedilol in healthy volunteers. Arzneimittelforschung 2005; 55: 212-217
15 Zarghi A, Foroutan SM, Shafaati A et al. Quantification of carvedilol in human plasma by liquid chromatography using fluorescence detection: application in pharmacokinetic studies. J Pharm Biomed Anal 2007; 44: 250-253
16 Rathod R, Prasad LP, Rani S et al. Estimation of carvedilol in human plasma by using HPLC-fluorescence detector and its application to pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 857: 219-223
17 do Carmo Borges NC, Mendes GD, de Oliveira Silva D et al. Quantification of carvedilol in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry: application to bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 822: 253-262
18 Li XN, Dai PF, Ge QH et al. Bioequivalence of domestic and imported carvedilol tablets. Chinese J of Clin Pharmacy 2006; 15: 29-31
19 Sehrt D, Meineke I, Tzvetkov M et al. Carvedilol pharmacokinetics and pharmacodynamics in relation to CYP2D6 and ADRB pharmacogenetics. Pharmacogenomics 2011; 12: 783-795
20 Shin J, Johnson JA. Beta-blocker pharmacogenetics in heart failure. Heart Fail Rev 2010; 15: 187-196
21 CPMP (Committee for Proprietary Medicinal Products): Note For Guidance on the Investigation of Bioavailability and Bioequivalence 2001
22 U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System