Abstract
We studied the use of atrioventricular (AV) conduction time to assess the therapeutic equivalence of two diltiazem formulations in 20 volunteers in a double-blind, cross-over trial. ECG recording was carried out before and at several intervals after drug administration, and prolongation of the PQ interval (ΔPQ) was taken as a pharmacodynamic response. In addition, diltiazem plasma concentrations were determined in 8 subjects.
The effect of diltiazem increased proportionally with the plasma concentration and could be detected up to 10 h after administration. The area under the effect-time curve (AUEC0–10), the peak effect (Emax), and the effect mean residence time (MRTE) showed significant differences. In contrast to the pharmacodynamics, the pharmacokinetic profiles of diltiazem do not vary to the same extent.
We conclude that the formulations are therapeutically different. Furthermore, at the administered dose, ΔPQ appears to be a sensitive measure for assessing the electrophysiological properties of diltiazem.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Araki H, Hotokebushi N, Ohta T, Sakaino N, Nishi K (1986) Effects of diltiazem on PR intervals in healthy young adults. Clin Ther 8: 196–202
Bourassa MG (1985) Haemodynamic and electrophysiologic effects of diltiazem. Acta Pharmacol Toxicol 57 [Suppl II]: 21–30
Boxtel CJ van, Jonkers RE (1992) Combined drug action. In: Boxtel CJ van, Holford NHG, Danhof M (eds) The in vivo study of drug action. Elsevier, Amsterdam, 93–105
Boyd RA, Chin SK, Don-Pedro O, Verotta D, Sheiner LB, Williams RL, Giacomini KM (1989) The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose. Clin Pharmacol Ther 46: 408–419
Buckley MM-T, Grant SM, Goa KL, McTavish D, Sorkin EM (1990) Diltiazem — a reappraisal of its pharmacological properties and therapeutic use. Drugs 39: 757–806
Carruthers SG, McCall B, Cordel BA, Wu R (1987) Relationship between heart rate and PR interval during physiological and pharmacological interventions. Br J Clin Pharmacol 23: 259–265
Clozel J, Billette J, Caillé G, Théroux P, Cartier R (1984) Effects of diltiazem on atrioventricular conduction and arterial blood pressure: correlation with plasma drug concentrations. Can J Physiol Pharmacol 62: 1479–1486
Erb KA, Wolf GK, Belz GG (1991) Prüfung der pharmakodynamischen Äquivalenz von Glyceroltrinitrathaltigen Sprays zur oralen Anwendung mit und ohne Fluor-Chlor-Kohlenwasserstoffe. Arzneimittelforschung / Drug Res 41: 484–488
Food and Drug Administration (1977) Bioavailability and bioequivalence requirements. Code of Federal Regulations CFR 42: 1624–1652
Fukuhara S, Echizen H, Naito M, Ishikawa S, Toyama M, Nagoshi H, Honda M, Ishizaki T (1989) An interindividual variability in the sensitivity of atrioventricular node to diltiazem in patients with PSVT. J Clin Pharmacol 29: 102–106
Gordin A, Pohto P, Sundberg S, Nykonen S, Haataja H, Monnistö P (1986) Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers. Eur J Clin Pharmacol 31: 423–426
Holford NHG, Sheiner LB (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6: 429–453
Huber T, Merz P-G, Harder S (1991) Bioverfügbarkeit und hämodynamische Wirkungen nach Applikation von sublingualem Glyceroltrinitrat. Arzneimittelforschung / Drug Res 41: 715–718
Kelly JG, O'Malley K (1992) Clinical pharmacokinetics of calcium antagonists. An update. Clin Pharmacokinet 22: 416–433
Kümmerle H-P (1981) Methoden der klinischen Pharmakologie. Urban and Schwarzenberg, München, pp 321–392
Steinijans VW, Diletti E (1983) Statistical analysis of bioavailability studies: parametric and nonparametric confidence intervals. Eur J Clin Pharmacol 24: 127–136
Steinijans VW, Diletti E (1985) Generalization of distribution free confidence intervals for bioavailability ratios. Eur J Clin Pharmacol 28: 85–88
Veng-Pedersen P (1989) Mean time parameters in pharmacokinetics. Definition, computation and clinical implications. Clin Pharmacokinet 17: 424–440
Yeung PK, Mosher SJ, Quilliam MA, Montague TJ (1990) Species comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits and rats. Drug Metab Dispos Bio Fate Chem 18: 1055–1059
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Della Paschoa, O.E., Luckow, V., Trenk, D. et al. Prolongation of the PQ interval as a measure of therapeutic inequivalence between two formulations of diltiazem. Eur J Clin Pharmacol 48, 45–49 (1995). https://doi.org/10.1007/BF00202171
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00202171