Skip to main content
SpringerLink
Log in

Bioequivalence of a Highly Variable Drug: An Experience with Nadolol

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC∞, and Cmax in bioequivalence determinations.

Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax.

Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC∞. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects.

Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. A. H. Jiminez, G. H. Tofler, X. Chen, M. E. Stubbs, H. S. Solomon, and J. E. Muller. Effects of nadolol on hemodynamic and hemostatic responses to potential mental and physical triggers of myocardial infarction in subjects with mild systemic hypertension. Amer. J. Cardiol. 72:47–52 (1993).

    Google Scholar 

  2. J. Bonelli, W. Waldhausl, D. Magometschnigg, J. Schwarzmeier, A. Korn, and G. Hitzenberger. Effects of exercise and of prolonged oral administration of propranolol on hemodynamic variables, plasma renin concentration, plasma aldosterone, and cAMP. Europ. J. Clin. Invest. 7:337–343 (1977).

    Google Scholar 

  3. R. A. Vukovich, J. E. Foley, B. Brown, D. A. Willard, M. Buckley, D. O'Kelly, D. Fitzgerald, W. Tormey, and A. Darragh. Effects of β-blockers on exercise double product. Brit. J. Clin. Pharm. 7:167S–172S (1979).

    Google Scholar 

  4. K. L. Duchin, R. A. Vukovich, L. G. Dennick, J. T. Groel, and D. A. Willard, Effects of nadolol β-blockade on blood pressure in hypertension. Clin. Pharmacol. Therap. 27:57–63 (1980).

    Google Scholar 

  5. J. Dreyfuss, D. L. Griffith, S. M. Singvhi, J. M. Shaw, J. J. Ross, R. A. Vukovich, and D. A. Willard. Pharmacokinetics of nadolol, a beta-receptor antagonist: Administration of single and multiple-dose regimens to hypertensive patients. J. Clin. Pharmacol. 19:712–720 (1979).

    Google Scholar 

  6. R. A. Morrison, S. M. Singvi, W. A. Creasey, and D. A. Willard. Dose proportionality of nadolol pharmacokinetics after intravenous administration in healthy subjects. Eur. J. Clin. Pharmacol. 33:625–628 (1988).

    Google Scholar 

  7. D. G. McDevitt. Comparison of pharmacokinetic properties of beta-adrenoceptor blocking agents. Eur. Heart. J. 8:9–14 (1987).

    Google Scholar 

  8. J. Herrera, R. A. Vukovich, and D. L. Griffith. Elimination of nadolol in patients with renal impairment. Br. J. Clin. Pharmacol. 7:227S–231S (1979).

    Google Scholar 

  9. J. J. Krukemeyer, H. Buodoulas, P. F. Binkley, and J. J. Lima. Comparison of single-dose and steady-state nadolol plasma concentrations. Pharm. Res. 7:953–956 (1990).

    Google Scholar 

  10. M. Schafer-Korting, N. Bach, H. Knauf, and E. Mutschler. Pharmacokinetics of nadolol in healthy subjects. Eur. J. Clin. Pharmacol. 26:125–127 (1984).

    Google Scholar 

  11. GUIDANCE, Nadolol Tablets: In Vivo Bioequivalence and In Vitro Dissolution, Division of Bioequivalence, Office of Generic Drugs, U. S. Food and Drug Administration, May 16, 1992.

  12. R. G. Buice, V. Subramanian, and E. Lane. Bioequivalence of two orally-administered nicardipine products. Biopharm. Drug. Disp. in press.

Download references

Author information

Authors and Affiliations

  1. Scientific Operations, Zenith-Goldline Pharmaceuticals, Northvale, New Jersey

    Robert G. Buice, Veerappan S. Subramanian & Samuel Uko-Nne

  2. Clinical Pharmacology, Baker-Norton Pharmaceuticals, Miami, Florida

    Kenneth L. Duchin

Authors
  1. Robert G. Buice
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Veerappan S. Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth L. Duchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel Uko-Nne
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buice, R.G., Subramanian, V.S., Duchin, K.L. et al. Bioequivalence of a Highly Variable Drug: An Experience with Nadolol. Pharm Res 13, 1109–1115 (1996). https://doi.org/10.1023/A:1016031313065

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016031313065

Search

Navigation