Skip to main content
SpringerLink
Log in

Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and (3) clinical perception upon application.

Pharmacokinetically, the time courses of the plasma concentrations of GTN and its dinitrate metabolites, 1,2- and 1,3-GDN, subsequent to the sublingual administration of 0.8 mg GTN showed somewhat lower bioavailability of GTN and its metabolites than to the reference. Pharmacodynamically, the changes in the DPG signals after the application of 0.8 mg GTN with TL were biostatistically euivalent with R (estimated ratio TL/R for the maximum decrease of the ratio between the systolic a wave and c incisure: 0.98; 90% CI: 0.84–1.14; and for the average decrease of the c: a ratio: 0.97; 90% CI: 0.80–1.16). The time of occurrence of the maximum effect of TL was not significantly different from that of R (estimated difference TL-R: -2.25 min; 95% CI:-9.5 min to 2 min).

In contrast, after the administration of an FCH-free GTN spray with a higher ethanol content (TH, active control), the effect had a slightly earlier onset (TH-R:-6 min, 95% CI: -9.5 to -2 min) and there was a higher average response (TH/R: 1.12: 90% CI: 0.95 to 1.34). However, TH was consistently judged to cause an extremely unpleasant burning sensation in the mouth and thus was perceived as distinctly different from R. In contrast, TL was well tolerated and could not be distinguished from R.

Therefore only TL met the criteria of overall therapeutic equivalence to R.

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. Murell W (1879) Nitroglycerin as a remedy for angina pectoris. Lancet I:80, 113, 225, 284, 642–646

    Google Scholar 

  2. Thadani U, Opie LH. Nitrates (1987) In: Opie LH, Chatterjee K, Gersh BJ, Harrison DC, Kaplan NM, Marcus FI, Singh BN, Sonnenblick EH, Thadani U (eds) Drugs for the heart. Grune & Stratton, Orlando, pp 19–33

    Google Scholar 

  3. Silber S (1990) Nitrates: why and how should they be used today?. Eur J Clin Pharmacol 38[Suppl 1]:S35-S51

    Google Scholar 

  4. Nast HP (1988) Hypertensive Krise: Nitroglycerin- oder Nifedipin-Kapseln geben? Therapiewoche 38:3898–3903

    Google Scholar 

  5. Scholze J, Matzke J, Linss G (1991) Nitroglyzerin in der Behandlung hypertensiver Krisen bei niereninsuffizienten Patienten. Nieren Hochdruckkrankh 20:701–707

    Google Scholar 

  6. Mügge A, Förstermann U, Lichtlen PR (1989) Endotheliale Funktionen bei kardiovaskulären Erkrankungen. Z Kardiol 78:147–160

    Google Scholar 

  7. Lüscher TF (1989) Endothelium-derived relaxing and contracting factors: potential role in coronary artery disease. Eur Heart J 10:847–857

    Google Scholar 

  8. Sanders PW (1992) Role of nitric oxide in regulation of blood pressure. J Nephrol 5:23–30

    Google Scholar 

  9. Abrams J, Abuquerque NM (1985) Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 110:216–224

    Google Scholar 

  10. Winsor T, Karpman HL (1958) Waves of the digital plethysmogram. Angiology 9:202–207

    Google Scholar 

  11. Gumbleton M; Benet LZ (1991) Pharmacological activity of the dinitrate metabolites of nitroglycerin following their oral administration to healthy volunteers. Br J Clin Pharmacol 31:211–213

    Google Scholar 

  12. Sickmüller B (1990) FCKW: weitere nationale und internationale Einschränkungen vorgesehen. Pharm Ind 52:290–308

    Google Scholar 

  13. FCKW-Aerosole im medizinischen Bereich (1989) Gegenwärtiger Diskussionsstand und Positionspapier des Bundesverbandes der Pharmazeutischen Industrie e. V. Pharm Ind 51:616–632

    Google Scholar 

  14. Blume H et al (1991) ZL-Monographie Glceroltrinitrat (GTN). Dtsch Apoth Ztg 131:367

    Google Scholar 

  15. Huber T, Merz PG, Harder S, Rietbrock N (1990) Bioequivalence of sublingual glycerol trinitrate. Bioavailability and haemodynamic effects after application of a fluorochlorohydrocarbons-dependent spray and a new pumping system. Drug Res 40:1319–1322

    Google Scholar 

  16. Huber T, Merz MG, Harder S (1991) Bioverfügbarkeit und hämodynamische Wirkungen nach Applikation von sublingualem Glyceroltrinitrat. Ein neues Freisetzungssystem. Drug Res 41:715–718

    Google Scholar 

  17. Erb K, de Mey C, Zimmermann T, Mutschler H, Roll S, Belz GG (1994) Pharmakodynamische Äquivalenz und klinische Verträglichkeit eines neuen FCKW-freien Glyceroltrinitratsprays mit niedrigem Ethanol-Gehalt im Vergleich zu einem FCKW-haltigen Referenzspray und einem FCKW-freien Pumpspray mit höherem Ethanol-Gehalt. Arzneim Forsch 44:478–482

    Google Scholar 

  18. Good clinical practice for trials on medicinal products in the European Community. Note for Guidance II/3976/88-EN, 4.5.90

  19. Lund F (1986) Digital pulse plethysmography (DPG) in studies of the hemodynamic response to nitrates — a survey of recording methods and principles of analysis. Acta Pharmacol Toxicol 59(suppl. VI):79–96

    Google Scholar 

  20. V. Kries J (1892) Studien zur Pulslehre. Mohr, Freiburg, pp 119–126)

    Google Scholar 

  21. Erb KA, de Mey C, Wolf GK, Kroll M, Belz GG (1991) Prüfung der pharmakodynamischen Äquivalenz Glyceroltrinitrathaltigen Sprays zur oralen Anwendung mit und ohne Fluor-Chlor-Kohlenwasserstoffe. Arzneimittelforschung/Drug Res 41:484–488

    Google Scholar 

  22. Porchet H, Bircher J (1982) Noninvasive assessment of portal-systemic shunting: evaluation of a method to investigate systemic availability of oral nitroglyceryl trinitrate by digital plethysmography. Gastroenterology 82:629–637

    Google Scholar 

  23. Isenschmid M, Müller M, Bührer, Vorkauf H, Bircher J (1985) Absolute bioavailability of glyceryl trinitrate from a transdermal system, assessed by digital plethysmography. Int J Clin Pharmacol Ther Tox 23:345–351

    Google Scholar 

  24. Belz GG (1985) Nitrattherapie. In: Hochrein H, Bussmann WD (eds) Perimed, Erlangen, pp 55–61

    Google Scholar 

  25. Yee KF (1986) The calculation of probabilities in rejecting bioequivalence. Biometrics 42:961–965

    Google Scholar 

  26. Meineke I (1987) A simple BASIC program for the calculation of nonparametric confidence intervals in bioequivalence testing. Comp Methods Progr Biomed 24:65–71

    Google Scholar 

  27. Meineke I, de Mey C (1991) Another simple BASIC-program for the assessment of bioequivalence in a two-period crossover design. Comp Methods Progr Biomed 35:1521-RR

    Google Scholar 

  28. APV Guideline (1987) Studies on bioavailability and bioequivalence. Drugs Made in Germany 30:161–166

    Google Scholar 

  29. CPMP Working Party on the Efficacy of Medicinal Products (1991) Note for guidance: investigation of bioavailability and bioequivalence. Commission of the European Communities, III/5489-EN

  30. Food and Drug Administration (1977) Drug products: bioequivalence requirements and in-vivo bioavailability (Dept., Health, FDA). Fed Regi III, 42:1624–1653

    Google Scholar 

  31. Food and Drug Administration (1984) Code of federal regulations. General provisions: procedures for determining the bioavailability of drug products: bioequivalence requirements. FDA, Washington DC 21:117–135

    Google Scholar 

  32. Food and Drug Administration (1988) Report by the bioequivalence task force on recommendations from the bioequivalence hearing conducted by the FDA (29 Sep.-1 Oct 1986) FDA, Washington DC

    Google Scholar 

  33. Nordic Council on Medicines (1987) Bioavailability studies in man. Nordic guidelines. NLN Publication 18, Nordiska Läkemedelsnämnden, Upsala

    Google Scholar 

  34. Schulz HU, Steinijans VW (1991) Striving for standards in bioequivalence assessment: a review. Int J Clin Pharmacol Ther Toxicol 29:293–298

    Google Scholar 

  35. Jähnchen E (1986) Relationship between pharmacokinetics and pharmacodynamics of organic nitrates. Z Kardiol 75[Suppl 3]:12–15

    Google Scholar 

  36. Bogaert M (1987) Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations. Clin Pharmacokinet 12:1–11

    Google Scholar 

  37. Jaeger H et al. (1987) Determination of nitrates in plasma. Drugs 33:9–22

    Google Scholar 

  38. Food and Drug Administration (1977) Single-entity coronary vasodilators. Drugs for human use; drug efficacy study implementation. Permission for drugs to remain on the market. Amendment. Fed Reg 42:43127–43131

    Google Scholar 

  39. Smolen VF (1976) Theoretical and computational basis for drug bioavailability determinations using pharmacological data. I. General considerations and procedures. J Pharmacokinet Biopharm 1976;4:337–353

    Google Scholar 

  40. Smolen VF (1976) Theoretical and computational basis for drug bioavailability determinations using pharmacological data. II. Drug input-response relationships. J Pharmacokinet Biopharm 4:355–375

    Google Scholar 

  41. Smolen VF (1978) Bioavailability and pharmacokinetic analysis of drug responding systems. Ann Rev Pharmacol Toxicol 18:495–522

    Google Scholar 

  42. Buschmann M, Wiegand A, Schnellbacher K, Bonn R, Rehe A, Trenk D, Jähnchen E, Roskamm H (1993) Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve. Eur J Clin Pharmacol 44:451–456

    Google Scholar 

  43. Smolen VF (1978) Bioavailability and pharmacokinetic analysis of drug responding systems. Ann rev Pharmacol Toxicol 18:495–522

    Google Scholar 

  44. Dollery CT (1973) Editorial. Eur J Clin Pharmacol 6:1

    Google Scholar 

Download references

Author information

Author notes

  1. C. de Mey

    Present address: Boehringer Ingelheim, Humanpharmakologisches Zentrum, D-55216, Ingelheim am Rhein, Germany

Authors and Affiliations

  1. Centre for Cardiovascular Pharmacology, Alwinenstrasse 16, D-65189, Wiesbaden, Germany

    C. de Mey, K. Erb, H. Mutschler & G. G. Belz

  2. Pohl-Boskamp GmbH & Co, Kielerstrasse 11, D-25551, Hohenlockstedt, Germany

    T. Zimmermann

  3. Zentrallaboratorium Deutscher Apotheker, Gianheimerstrasse 20, D-65760, Eschborn, Germany

    H. Blume

Authors
  1. C. de Mey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Erb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Mutschler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. G. Belz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Blume
    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

de Mey, C., Erb, K., Mutschler, H. et al. Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray. Eur J Clin Pharmacol 47, 437–443 (1995). https://doi.org/10.1007/BF00196858

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00196858

Key words

Search

Navigation