Bioequivalence study of two formulations of bisoprolol fumarate film-coated tablets in healthy subjects

Raymond R Tjandrawinata, Effi Setiawati, Danang Agung Yunaidi, Iwan Dwi Santoso, Arini Setiawati, Liana W Susanto, Raymond R Tjandrawinata, Effi Setiawati, Danang Agung Yunaidi, Iwan Dwi Santoso, Arini Setiawati, Liana W Susanto

Abstract

Background: The present study was conducted to compare the bioavailability of two bisoprolol fumarate 5 mg film-coated tablet formulations (test and reference formulations).

Patients and methods: This study was a randomized, single-blind, two-period, two-sequence crossover study that included 18 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were determined based on the concentrations of bisoprolol (CAS 66722-44-9), using ultraperformance liquid chromatography with a tandem mass spectrometer detector. In each of the two study periods (separated by a washout of 1 week) a single dose of test or reference product was administered. The pharmacokinetic parameters assessed were area under the plasma concentration-time curve from time zero to 48 hours (AUC(t)), AUC from time zero to infinity (AUC(inf)), the peak plasma concentration of the drug (C(max)), time needed to achieve C(max) (t(max)), and the elimination half-life (t(1/2)).

Results: The geometric mean ratios (90% confidence intervals) of the test drug/reference drug for bisoprolol were 101.61% (96.14%-107.38%) for AUC(t), 101.31% (95.66%-107.29%) for AUC(inf), and 100.28% (93.90%-107.09%) for C(max). The differences between the test and reference drug products for bisoprolol t(max) and t(1/2) values were not statistically significant (P > 0.05). There was no adverse event encountered during this bioequivalence test. The 90% confidence intervals of the test/reference AUC ratio and C(max) ratio of bisoprolol were within the acceptance range for bioequivalence.

Conclusion: It was concluded that the two bisoprolol film-coated tablet formulations (the test and reference products) were bioequivalent in terms of the rate and extent of absorption.

Keywords: antihypertension; bioavailability; bioequivalence; bisoprolol; pharmacokinetics; β1-adrenergic receptor antagonist.

Figures

Figure 1
Figure 1
Chemical structure of bisoprolol (CAS 66722-44-9).
Figure 2
Figure 2
Mean plasma concentrations versus time profiles of bisoprolol in human subjects (n = 18) after single-dose oral administration of 5 mg bisoprolol fumarate filmcoated tablet of the test drug and the reference drug.

References

    1. Lancaster SG, Sorkin EM. Bisoprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and angina pectoris. Drugs. 1988;36(3):256–285.
    1. Concor® 5 and Concor® 10 film-coated tablets [package insert] [Accessed July 27, 2012]. Available from: .
    1. Sweetman SC. Martindale: The Complete Drug Reference. 36th ed. New York: Pharmaceutical Press; 2009. p. 1234.
    1. The European Agency for the Evaluation of Medicinal Products (EMA), Committee for Proprietary Medicinal Products (CPMP) Note for Guidance on the Investigation of Bioavailability and Bioequivalence. [Accessed September 26, 2012]. Available from: .
    1. Badan Pengawas Obat dan Makanan Republik Indonesia (BPOM RI) Pedoman Uji Bioekuivalensi [Indonesian Guideline for Bioequivalence Studies] Jakarta: BPOM; 2004.
    1. World Medical Association. Declaration of Helsinki Recommendations Guiding Physicians in Biomedical Research Involving Human Patients. Amended by the 52nd WMA General Assembly; Edinburgh, Scotland. 2000.
    1. International Conference on Harmonisation (ICH) Expert Working Group. Guideline for Good Clinical Practice E6 (R1) Geneva: ICH; 1996. ICH Harmonized Tripartite Guideline.
    1. Organization for Economic Co-operation and Development (OECD) OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring Number 1: OECD Principles on Good Laboratory Practice. Paris: OECD; 1997.
    1. Bhatt J, Subbaiah G, Kambli S, et al. A high throughput and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the estimation of bisoprolol in human plasma using multiplexing technique. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;852(1–2):374–381.
    1. Gabriela P, Corneliu O, Aurel V. Experimental research for determination of bisoprolol fumarate in human plasma samples using liquid chromatographytandem mass spectrometry (LC-MS/MS) technique. Rom Biotechnol Lett. 2010;15(2):5140–5145.
    1. Diletti E, Hauschke D, Steinijans VW. Sample size determination for bioequivalence assessment by means of confidence intervals. Int J Clin Pharmacol Ther Toxicol. 1991;29(1):1–8.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe