A Comparative Single Dose Bioequivalence Study of Extended Release Antihypertensive Drug Formulation among Healthy Human Volunteers

Abstract

The objective of this study was to compare the in vivo characteristics of diltiazem extended release formulations for once daily, which were expected to be bioequivalent. Either two capsules of a test formulation or a 1 of the reference formulation, both containing 360 mg diltiazem were administered to healthy male volunteers after keeping fast of ten hour in a randomized, open label,three period crossover design. Plasma samples obtained over the subsequent period of 72 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical. The 90% CI for the log transformed data for Cmax, AUC0-t,AUC0-∞ for both the test product fell in the prescribed limits of bioequivalence for narrow therapeutics index drugs i.e. 80 to 120%. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in healthy, male volunteers under fasting

Keywords

• Diltiazem, bioequivalence, bioavailability

A Comparative Single Dose Bioequivalence Study of Extended Release Antihypertensive Drug Formulation among Healthy Human Volunteers

Öz

Bu çalışmanın amacı, biyolojik olarak eşdeğer olması beklenen, günde bir defalık diltiazem uzatılmış salınım formülasyonlarının in vivo özellikleri karşılaştırmaktı. Her ikisi de 360 mg Diltiazem ihtiva eden bir test formülasyonun iki kapsülü veya referans formülasyonun 1 kapsülü, on saat aç bekletildikten sonra sağlıklı erkek gönüllülere randomize, açık etiketli, üç periyotlu çapraz tasarımda verilmiştir. Üzerinden 72 saat süre geçtikten sonra elde edilen Plazma numuneleri geçerli bir LC-MS/MS yöntemi kullanılarak analiz edildi. Çalışma ilaçlarının güvenlik profili ve tolere edilebilirliği vital bulguların ölçümü, elektrokardiyografi ve klinik ile elde edilen yan etkilerin analizi ile değerlendirildi. Cmax log dönüştürülmüş verileri için 90% CI, AUC0-t,AUC0-∞ her iki ilaç için dar terapötik indeks ilaçlar için biyoeşdeğerliliğin öngörülen limitleri içine düştü, örneğin 80- 120%. Bu tek doz çalışma tespit etmiştir ki test ve referans ürünler açlık altında sağlıklı, erkek gönüllülerde biyoeşdeğerlik için düzenleyici kriterleri karşılamaktadır

Anahtar Kelimeler

• Diltiazem, biyoeşdeğerlik, biyoyararlanım

References

1. Koch-Wesser J. Serum drug concentrations as therapeutic guides. N Engl J Med 1982;287:227-31.
2. Benet LZ, Goyan JE. Bioequivalence and narrow thera- peutic index drugs Pharmacotherapy 1995;15:433-40.
3. Buckley MM-T, Grant SM, Goa KL, et al. Diltiazem: A reap- praisal of its pharmacologic properties and therapeutic use. Drugs 1990;39:757-806.
4. Katzung BG, Chatterjee K. Vasodilators and the treat- ment of angina pectoris. In: Katzung BG, ed. Basic Clinical Pharmacology. 4th ed. Norwalk, Conn: Appleton & Lange; 1989:140-51.
5. Nikkila MT, Inkovaara JA, Heikkinen JT, Olsson S-ORI Antihypertensive effect of diltiazem in a slow-release formulation for mild to moderate essential hypertension. Am J Cardiol 1989;63:1227-30.
6. Andrtn L, Htglund P, DotevaU A, et al. Diltiazem in hy- pertensive patients withtype II diabetes mellitus. Am J Cardiol1988;62:114G-20G.
7. Ginsberg D, Pappas JE, Rofman BA, et al. Once-daily dosing of sustained-release diltiazem capsules in mild- to-moderate hypertension. J Am Osteopath Assoc 1988;88:1489-92.
8. Pool PE, Massie BM, Venkataraman K, et al. Diltiazem as monotherapy for systemic hypertension: A multicenter, randomized, placebo-controlled trial. Am J Cardiol 1986;57:212-7.

9. Pool PE, Herron JM, Rosenblatt S, et al. Metabolic effects of antihypertensive therapy with a calcium antagonist. Am J Cardiol 1988;62:109G-13G.
10. Szlachcic J, Hirsch T, Tubau JF, et al. Diltiazem versus propranolol in essential hypertension: Responses of rest and exercise blood pressure and effects on exercise ca- pacity. Am J Cardiol 1987;59:393-9.
11. Frishman WH, Zawada ET Jr, Smith LK, et al. Comparison of hydrochlorothiazide and sustained-release diltia- zem for mild to- moderate systemic hypertension. Am J Cardiol 1987;59:615-23.
12. Leary WP, van der Byl K. Diltiazem compared with hy- drochlorothiazide in the treatment of mild-to-moderate essential hypertension. S Afr Med J 1988;74:13-5.
13. Leehey WE Hartman E. Comparison of diltiazem and hy- drochlorothiazide for treatment of patients 60 years of age and older with systemic hypertension. Am J Cardiol 1988;62:1218-3
14. Frishman WH, Charlap S, Goldberger J, et al. Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol 1985; 56:41H-6H.
15. Schulte K-L, Meyer-Sabellek WA, Haetenberger A, et al. Antihypertensive and metabolic effects of diltiazem and nifedipine. Hypertension 1986;8:859-65.
16. Simic D, Jurman V. Effects of diltiazem and nife- dipine on blood pressure. J Cardiovasc Pharmacol 1988;12(Suppl):S220-1.
17. Török E, Wagner M, Podmaniczky M. Comparison of urapi- dil and atenolol in hypertension. Drugs. 1988;35 Suppl 6:164-72.
18. Massie B, MacCarthy EP, Ramanathan KB, et al. Diltiazem and propranolol in mild to moderate essential hyperten- sion as monotherapy or with hydrochlorothiazide. Ann Intern Med 1987;107:150-7.
19. Weiss RJ, Bent B. Diltiazem-induced left ventricular mass regression in hypertensive patients. J Clin Hypertens 1987;3: 135-43.
20. Buckley MM-T, Grant SM, Goa KL, McTabish D, Sorkin EM. Diltiazem. A reappraisal of its pharmacological proper- ties and therapeutic use. Drugs 1990;39:757–806.
21. CDSCO (Central Drug Standard Control Organization), 2005, Guidelines for Bioavailability and Bioequivalence. Retrieved from http://cdsco.nic.in/html/BE%20 Guidelines%20Draft%20Ver10%20March%2016,%2005.pdf, accessed on 12 March 2008
22. European Medicines Agency, ICH Topic E6 (R1) Note for guidance on good clinical practice (CPMP/ICH/135/95), 2002.
23. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; Note of Clarification on Paragraph 29, Washington 2002; Note of Clarification on Paragraph 30, Tokyo 2004.
24. Chow CS, Liu JP: Design and analysis of bioavailability and bioequivalence studies. New York: Marcel Dekker; 1992:1–2.
25. US Food and Drug Administration (FDA): Guidance: statis- tical procedure for bioequivalence studies using standard 2-treatment cross-over design. Statement under 21 CRF 10.9. Rockville, MD: US Department of Health and Human Services; 1992.
26. Committee for Proprietary Medicinal Products (CPMP) Working Party on the Efficacy of Medicinal Products: Note for guidance: investigation of bioavailability and bio- equivalence. Brussels; 1991.