Summary
In this review, several deficiencies of publisged bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care.
A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test : reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made.
With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. SOme bioequivalence studies of calcium antagonists are deficient in this respect.
To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. SOme calcium antagonists, such as verpamil, show stereoselective pharmacokinetics, so that enantiomers may have to be investigated.
Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory
Similar content being viewed by others
References
Van Zwieten PA, Pfaffendorf M. Similarities and differences between calcium antagonists: pharmacological aspects. J Hypertens 1993; 11Suppl. 1: S3–11
Borcherding SM, Meeves SG, Klutman NE, et al. Calcium-channel antagonists for prevention of atherosclerosis. Ann Pharmacother 1993; 27: 61–7
Rameis H. On the principles of pharmacokinetics and pharmacodynamics of calcium antagonists [in German]. WMW 1993; 19: 490–9
Psaty BM, Heckbert S. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5
Furberg, CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31
Dougall HT, McLay J. A comparative review of the adverse effects of calcium antagonists. Drug Saf 1996; 15: 91–106
Henahan S. Clash of opinions in calcium antagonist controversy. Inpharma 1995; 1018: 3–4
Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation 1995; 92: 1068–73
Messerli FH. Case-control study, meta-analysis, and bouillabaisse: putting the calcium antagonist scare into context. Ann Intern Med 1995; 123: 888–9
Wagenknecht LE, Furberg CD, Hammon JW, et al. Surgical bleeding: unexpected effects of a calcium antagonist. BMJ 1995; 310: 776–7
Skelly JP, Barr WH, Benet LZ, et al. Report of the workshop on controlled-release dosage forms: issues and controversies. Pharm Res 1987; 4: 75–7
Skelly JP, Amidon GL, Barr WH, et al. In vitro and in vivo testing and correlation for oral controlled/modified-release dosage forms. Pharm Res 1990; 7: 975–82
Oral extended (controlled) release dosage forms. In vivo bioequivalence and in vitro dissolution testing. Rockville, MD: Division of Bioequivalence, Office of Generic Drugs, Food and Drug Administration, 1993
Statistical procedures for bioequivalence studies using a standard two-treatment crossover design. Rockville, MD: Division of Bioequivalence, Office of Generic Drugs, Food and Drug Administration, 1992
Investigation of bioavailability and bioequivalence. In: The rules governing medicinal products in the European Community. Vol. III; Addendum No 2. Luxemburg: Office for Official Publications of the European Communities, 1992: 149–68
Argenti D, Huang M-Y, Heald D, et al. Comparative pharmacokinetics and bioavailability of Dilacor XR and Cardizem CD in healthy volunteers. Am J Ther 1995; 2: 20–30
Lippert CL, Arumugham T, Bhargava VO, et al. The relative bioavailability of two marketed controlled-release diltiazem dosage forms at steady-state in healthy volunteers. Biopharm Drug Dispos 1996; 17: 43–53
Guimont S, Landriault H, Klischer K, et al. Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers. Biopharm Drug Dispos 1993; 14: 767–78
Smith MS, Verghese CP, Shand DG, et al. Pharmacokinetic and pharmacodynamic effects of diltiazem. Am J Cardiol 1983; 51: 1369–74
Hermann PH, Rodger SD, Remones G, et al. Pharmacokinetics of diltiazem after intravenous and oral administration. Eur J Clin Pharmacol 1983; 24: 349–52
Kolle EU, Ochs HR, Vollmer K-O. Pharmacokinetic model of diltiazem. Arzneimittel Forschung 1983; 33: 972–7
Caille G, Boucher S, Spenard J, et al. Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses. Eur J Drug Metab Pharmacokinet 1991; 16: 75–80
Rubio M, Masana MI, Garcilazo E, et al. Bioequivalence of two pharmaceutical forms of diltiazem. Biopharm Drug Dispos 1990; 11: 77–83
Schall R, Müller FO, Hundt HKL, et al. Relative bioavailability of four controlled-release nifedipine products. Biopharm Drug Dispos 1994; 15: 493–503
Tröger U, Martens J, Meyer FP, et al. Study on the bioequivalence of an oral nifedipine formulation and a sustained release reference preparation after single dose and repeated doses. Arzneimittel Forschung 1995; 45: 1266–70
Seth P, Seth PL. An in-vivo bioequivalence study of a new nifedipine extended release dosage form, ‘Opticaps’. Drug Dev Industrial Pharm 1994; 20: 1605–12
Meyer FP, Banditt P. Investigation into the bioequivalence of two nifedipine controlled-release formulations after single application and in steady-state [in German]. Arzneimittel Forschung 1993; 43: 646–50
Meyer FP, Banditt P. Zum Nachweis der Bioäquivalenz von zwei Nifedipin-Formulierungen. Z Klin Med 1991; 46: 1141–4
Hermann R. Bioequivalence of a nifedipine extended release formulation compared to a standard formulation [in German]. Arzneimittel Forschung 1996; 46: 28–34
Waldman SA, Morganroth J. Effects of food on the bioequivalence of different verapamil sustained-release formulations. J Clin Pharmacol 1995; 35: 163–9
Kozloski GD, de Vito JM, Johnson JB, et al. Bioequivalence of verapamil hydrochloride extended-release pellet filled capsules when opened and sprinkled on food and when swallowed intact. Clin Pharm 1992; 11: 539–42
Devane JG, Kavanagh M, Kelly JG. Dose proportionality and steady-state bioequivalence of verapamil sustained-release pellet-filled capsules. Cur Ther Res 1991; 50: 720–30
Rietbrock N, Fischer A, Menke G. Bioequivalence of generic drugs and substitution. Slow release verapamil [in German]. Z Kardiol 1987; 76: 621–25
Rietbrock N. Stellungnahme zum vorangegangenen Leserbrief von M Gierend, I Pelzer, J Schmidt [letter]. Z Kardiol 1988; 77: 72–4
Gierend M, Pelzer I, Schmidt J. Sachliche Richtigstellung zu ‘Bioäquivalenz von Generika und Substitution: Beispiel retardiertes Verapamil’ [letter]. Z Kardiol 1988; 77: 69–71
Baarsma IP, Floris WW, Salm K, et al. Vergleich zweier Formulierungen mit retardiertem Verapamil. Med Welt 1987; 38: 1176–82
Morganroth J, Waldman SA. Improved sensitivity in detecting drug-induced alterations in the PR-interval when measured by a single cardiologist compared to automated computer analysis. Am J Cardiol 1993; 72: 834–6
Holmes DG, Kutz K. Bioequivalence of a slow-release and a non-retard formulation of isradipine. Am J Hypertens 1993; 6 Suppl.: 70S–3S
Steinijans VW, Hauschke D. Update on the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol 1990; 28: 105–10
Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1991; 29: 394–9
Schall R, Luus HG. Comparison of absorption rates in bioequivalence studies of immediate release drug formulations. Int J Clin Pharm Ther Toxicol 1992; 30: 153–9
Schall R, Luus HG, Steinijans VW, et al. Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations. Int J Clin Pharm Ther 1994; 32: 323–8
Sauter R, Steinijans VW, Diletti E, et al. Presentation of results from bioequivalence studies. Int J Clin Pharmacol Toxicol 1992; 30 Suppl.: S7–S30
Sahajwalla CG, Longstreth J, Karim A, et al. Bioavailability-bioequivalence of Calan SR, Verapamil CR and Calan-IR based on R-, S- and R,S-verapamil [abstract]. J Clin Pharm 1992; 32: 961–2
Jamali F. Stereochemistry and bioequivalence. J Clin Pharmacol 1992; 32: 930–4
Nerurkar SG, Dighe SV, Williams RL. Bioequivalence of race-mic drugs. J Clin Pharm 1992; 32: 935–43
Tokuma Y, Noguchi H. Stereoselective pharmacokinetics of dihydropyridine calcium antagonists. J Chromatogr A 1995; 695: 181–93
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schall, R., Müller, F.R., Müller, F.O. et al. Bioequivalence of Controlled-Release Calcium Antagonists. Clin. Pharmacokinet. 32, 75–89 (1997). https://doi.org/10.2165/00003088-199732010-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199732010-00004