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Reteplase - Formulation and Format (61)

Reteplase - Formulation and Format (61)

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Reteplase, a recombinant plasminogen activator

10.2.2



21 1



Purity



The purity of reteplase, determined by hgh resolution chromatographic

methods (Rp-HPLC and SE-HPLC) is as follows:

Reteplase protein makes up > 99.99% of the total protein.

Impurities:

E. coli protein

70 ppm

ETthrina trypsin irhbitor < 2 ppm

DNA< 25pg/lOU

Endotoxins< 5 E U / d

10.2.3



Solubility



Reteplase is poorly soluble in water and the usual buffers, and requires the

addition of stabilizers (e.g. amino acids such as argtnine).

10.2.4



Absorption spectra (visible, UV, IR)



The protein concentration is determined by measurement of the absorption

at 280 nm against the respective buffer as reference. With a light path of 1 cm

and a protein concentration of 1 m g M , the absorbance is 1.69.

10.2.5



Isoelectric point (IEP)



The IEP of reteplase calculated from the amino acid composition is 7.23

10.2.6



pH



The pH of the reconstituted medicinal product of reteplase is in the range

pH 7.0 to pH 7.4

10.2.7



Stability



If stored in the original package, the injection vials of reteplase 10 U are

stable for two years at temperatures of 2°C to 25°C. During prolonged

storage the powder should be protected from excessive exposure to light.

The lyophilisate is also stable if deep-frozen. Exposure to temperatures

above 25°C shortens the shelf-life; temperatures greater than 30°C should

be avoided.

After reconstitution as directed, the solution should be used immediately.

The reconstituted solution is chemically stable for 4 hours.



212



10.2.8



Dr Michael Waller and Dr Ulrich Kohnert

Nature and risk of the decomposition products



Decomposition results in transition to the two-chain form of reteplase.



10.3



Product presentation



10.3.1



Description



-



Reteplase is presented as a sterile, dry, white, lyophilized powder in a

glass vial, mostly adhering to the glass wall of the vial.

Each vial contains 1.16 g powder, equivalent to 10 U (a single dose) of

reteplase.

Each dose of the medxinal product contains 1.O mg polysorbate 20, plus

871.0 mg arginine and 268.6 mg phosphoric acid as stabilizers.

The powder is reconstituted with 10 ml diluent (water) for intravenous

injection.



10.3.2



Potency units



The potency of reteplase is gven in units (U) based on a reference

standard which is reteplase-specific and is not comparable with the units used

for other thrombolytic agents. The designation Mu (1 MU = 1 U) is also

sometimes used in publications.



BIOGRAPHY

Ulrich Kohnert was the Project Leader Biotechnology for the development

of reteplase. He is a chemist by training and has special expertise in in vitro

folding, purification and in vitro characterization of proteins, as well as the

development of pharmaceutical formulations for therapeutic proteins.

Boehringer Mannheim is a htgh technology company in the healthcare market.

It holds a leading position in research development and production of

diagnostics and new drugs. Biotechnology has a prominent position and long

tradition withtn the company profile. Boehringer Mannheim operates one of

Europe's largest biotechnology facilities in Penzberg, Bavaria. Boehringer

Mannheim GmbH is part of the Roche Deutschland Holding GmbH.



Reteplase, a recombinant plasminogen activator



213



REFERENCES

1. Gruppo Italian0 per lo Studio della Streptochinasi nell’hfarto miocardico (GISSI).

(1986). Effectiveness of intravenous thrombolytic treatment in acute myocardial

infarction. Lancet, 1, 871-874.

2. ISIS-2 (second International Study of Infarct Survival ) Collaborative Group. (1988).

Randomised trial of intravenous streptokinase, oral aspirin, both or neither among

17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet, 2, 349-360.

3. ISAM Study Group. (1986). A prospective trial of intravenous streptokinase in acute

myocardial infarction (ISAM). N. Engl. J. Med., 314, 1465-1471.

4. AIMS Trial Study Group. (1988). Effect of intravenous APSAC on mortality after acute

myocardial infarction: Preliminary report of a placebo-controlled clinical trial. Lancet,

1, 545-549.

5 . Wilcox, R.G. et al. (1988). Trial oftissue plasminogen activator for mortality reduction

in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis

(ASSET). Lancet, 2, 525-530.

6. White, H.D. et al. (1987). Effect of intravenous streptokinase on left ventricular function

and early survival after acute myocardial infarction. N. Engl. J. Med., 317, 850-855.

7. Van De Werf, F. and Arnold, A.E.R. (1988). Intravenous tissue plasminogen activator

and size of infarct, left ventricular function, and survival in acute myocardial infarction.

Br. Med. J., 297, 1374-1379.

8. GUSTO-Angiographic Investigators. (1993). The effects of tissue plasminogen activator,

streptokinase or both on coronary-artery patency, ventricular function and survival after

acute myocardial infarction. N. Engl. J. Med., 1329, 1615-1622.

9. Granger, C.B. et al. (1992). Thrombolytic therapy for acute myocardial infarction - a

review. Drugs, 44, 293-325.

10. Sobel, B.E. and Collen, D. (1992). Questions unresolved by the Third International

Study ofhfarct Survival. Am. J. Cardiol., 70, 385-389.

11. Bode, C. et al. (1997). Clinical trial results with a new plasminogen activator. European

Heart Journal, 18 (suppl F), F17-F21.

12. Kohnert, U. et al. (1992). Biochemical properties of the kringle 2 and protease domains

are maintained in the refolded t-PA deletion variant BM 06.022. Protein Eng., 5, 93-100.

13. Martin, U. et al. (1993). BM 06.022: A novel recombinant plasmhogen activator.

Cardiovasc. Drug Rev., 11, 299-3 11.

14. Braunwald, E. (1987). The path to myocardial salvage by thrombolytic therapy.

Circulation, 76(suppl II), 11-2 - II7.

15. Chazov, E.I. et al. (1976). Intracoronary administration of fibrinolysis in acute

myocardial infarction. Ter Arkh, 48, 8.

16. Rentrop, K.T. et al. (1979). Initial experience with transluminal recanalization of the

recently occluded infarct-related coronary artery in acute myocardial infarction.

Comparison with conventionally treated patients. Clin. Cardiol., 2, 92.

17. Blumgart, H.L. et al. (1941). Experimental studies on the effect of temporary occlusion

of coronary arteries. Am. J. Heart., 22, 374-389.

18. Smalling, R.W. and Hanna, G.P. (1966). Clinical pharmacology and mechanisms of

action of thrombolytic agents. In: CalBRM (ed.). Thrombolytic Therapy: New

Standards of Care, Part I: the Science of Plasminogen Activators. American Journal of

Cardiology. Belle Mead, NJ: Excerpta Medica, 9-15.

19. The GUSTO Investigators (1993). An international randomized trial comparing four

thrombolytic strategies for acute myocardial infarction. N. Engl. J. Med., 329, 673-682.



214



Dr Michael WalIer and Dr Ulrich Kohnert



20. Rapaport, E.(1992). The ideal thrombolytic agent. In: Sleight P, Tavavi L (eds). The

Major Clinical Trials on Thrombolysis for Acute Myocardial Infarction. New York:

Raven Press, 1-5.

21. Vahanian, A. (1996). Thrombolytic therapy in Europe: current status. Eur. Heart J.,

17(s~pplE),21-27.

22. S h e s , R.J. et al. (1995). Link between the angiographic substudy and mortality

outcomes in a large randomized trial of myocardial reperfusion: Importance of early and

complete artery reperfusion. Circulation, 91, 1923-1928.

23. Fischer, S . (1998). The molecular design of reteplase. Drugs of Today, 33, 641-648.

24. Bode, C. et al. (1996). The future of thrombolysis in the treatment of acute myocardial

infarction. Eur. Heart J., 17(suppl E), 55-60.

25. Fischer, S.and Kohnert, U. (1997). Major mechanistic differences explain the higher

clot lysis potency of reteplase over alteplase: lack of fibrin binding is an advantage for

bolus application of fibrin-specific thrombolytics. Fibrinolysis and Proteolysis, 11(3),

129-135.

26. Pennica, D. et al. (1983). Cloning and expression of human tissue-type plasminogen

activator cDNA in E. coli. Nature, 301, 214-221.

27. S m a h g , R.W. (1996). Molecular biology of plasminogen activators: What are the

clinical implications of drug design? Am. J. Cardiol., 78 (suppl 12A), 2-7.

28. Hotchkiss, A. et al. (1988). The influence of carbohydrate structure on the clearance of

recombinant tissue-type plasminogen activator. Thromb. Haemost., 60, 255-261.

29. Kohnert, U.et al. (1993). A variant tissue plasminogen activator (t-PA) comprised of

the kringle 2 and protease domain shows a significant difference in the in vitro rate of

plasmin formation as compared to the recombinant human t-PA fiom transformed

Chinese hamster ovary cells. Fibrinolysis, 7, 365-372.

30. Sprengers, E.D. and KIuft, C. (1987). Plasmhogen activator inhibitors. Blood, 69, 381387.

31. Ny, T. et al. (1984). The structure of the human tissue-type plasminogen activator gene:

correlation of intron and exon structures to functional and structural domains. Proc.

Natl. Acad. Sci., 81, 5355-5359.

32. Stem, A. et al. (1990). Gewebs-Plasminogenaktivator-Derivat. European Patent

Application 382174.

33. Maniatis, T. et al. (1992). Molecular Cloning: A Laboratory Manual. Cold Spring

Harbor, NY: Cold Spring Earbor Laboratory Press.

34. Brinkmann, U. et aZ. (1989). High-level expression of recombinant genes in

Escherichia coli is dependent on the availability of the dnaY gene product. Gene, 85,

109-114.

35. Rudolph, R. et al. (1987). Verfahren zur Aktiviemg von gentechnologisch

hergestellten, heterologen, Disulfidbriicken aufweisenden eukaryontischen Proteinen

nach Expression in Prokaryonten. European Patent Application 219874.

36. Rudolph, R. (1990). In: Tschesche H (ed.). Modem Methods in Protein and Nucleic

Acid Research. Berlin: Walter de Gruyter, 149-172.

37. Rudolph, R. and Fischer, S. (1990). Process for obtaining renatured proteins. United

States Patent, 4933434.

38. Heussen, C. et al. (1984). Purification of human tissue plasminogen activator with

EIythrina trypsin mhibitor. J. Biol. Chem., 259, 11635-11638.

39. Kruithof, E.K. et al. (1985). Human tissue-type plasminogen activator. Production in

continuous serum-free cell culture and rapid purification. Biochem. J., 226, 63 1-636.



Reteplme, a recombinant plasminogen activator



215



40. Verheijen, J.H. et al. (1982). A simple spectrophotometric assay for extrinsic (tissuetype) plasminogen activator applicable to measurements in plasma. Thromb.

Haemostas., 48(3), 266-269.

41. Kohnert, U. et al. (1996). The recombinant Escherichia coli-derived protease-domain of

tissue-type plasminogen activator is a potent and fibrin specifc fibrinolytic agent.

Fibrinolysis, 10, 83-102.

42. Martin, U. et al. (1992). Evaluation of thrombolytic and systemic effects of novel

recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase,

streptokinase and urokinase in a canine model of coronary artery thrombosis. J. Am.

Coll. Cardiol., 19, 433-440.

43. Martin, U. et al. (1992). Hirudin and sulotroban improve coronary blood flow after

reperfhion induced by the novel recombinant plasminogen activator BM 06.022 in a

canine model of coronary artery thrombosis. Int. J. Hematol., 56, 143-153.

44. Martin, U. et al. (1991). Pharmacokinetic properties of an Escherichia coli-produced

recombinant plasminogen activator (BM 06.022) in rabbits. Thromb. Res., 62, 137-146.

45. Martin, U. et al. (1992). Pharmacokinetics ofthe novel recombinant plasminogen

activator BM 06.022 in rats, dogs and non-human primates. Fibrinolysis, 6, 39-43.

46. Martin, U. et al. (1991). Dose-ranging study of the novel recombinant plasminogen

activator BM 06.022 in healthy volunteers. Clin. Pharmacol. Ther., 50, 429-436.

47. Seiiiied, E. et al. (1988). Pharmacokinetics of antigen and activity of recombinant

tissue-type plasminogen activator after infusion in healthy volunteers. Drug Res., 38,

418-422.

48. Seifkied, E. et al. (1992). Bolus application of a novel recombinant plasminogen

activator in acute myocardial infarction patients: Pharmacokinetics and effects on the

hemostatic system. Ann.N.Y. Acad. Sci., 667, 417-420.

49. Tebbe, U. et al. (1989). Single bolus injection of recombinant tissue-type plasminogen

activator in acute myocardial infarction. Am. J. Cardiol., 64, 448-453.

50. Martin, U. et al. (1991). Pharmacokinetic and hemostatic properties of the recombinant

plasminogen activator BM 06.022 in healthy volunteers. Thromb. Haemost., 66(5), 569574.

5 1. Neuhau,s K-L. et al. (1994). Dose finding with a novel recombinant plasminogen

activator (BM 06.022) in patients with acute myocardial infarction: Results ofthe

German recombinant plasminogen activator study. J. Am. Coll. Cardiol., 24, 55-60.

52. Tebbe, U. et al. (1993). Open, noncontrolled dose-finding study with a novel

recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with

acute myocardial infarction. Am. J. Cardiol.,72, 5 18-524.

53. Griinewald, M. et al. (1995). Single vs double bolus thrombolysis with the recombinant

plasminogen activator BM 06.022 in patients with acute myocardial infarction pharmacokinetics and hemostatic changes (abstract). Thromb. Haemost., 73, 1328.

54. Smalling, R.W. et al. (1995). More rapid, complete, and stable coronary thrombolysis

with bolus administration of reteplase compared with alteplase infusion in acute

myocardial infarction. Circulation, 91, 2725-2732.

55. Bode, C. et al. (1996). Randomized comparison of coronary thrombolysis achieved with

a double-bolus reteplase (recombinant plasminogen activator) and fiont-loaded,

accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute

myocardial infarction. Circulation, 94, 891-898.

56. International Joint Efficacy Comparison of Thrombolytics. (1995). Randomised, doubleblind comparison of reteplase double-bolus administration with streptokinase in acute

myocardial infarction (INJECT): trial to investigate equivalence. Lancet, 346, 329-336.



216



Dr Michael Waller and Dr Ulrich Kohnert



57. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III)

Investigators. (1997). A comparison of reteplase with alteplase for acute myocardial

infarction N. Ehg.1 J. Med., 337, 1118-1123.

58. Chesebro, J.H. et al. (1987). Thrombolysis in Myocardial Infarction 0

Trial, Phase

I: A comparison between tissue plasminogen activator and intravenous streptokinase.

Clinical findings through hospital discharge. Circulation, 76, 142-154.

59. Schroder, R. et al. (1995). Extent of early ST segment elevation resolution: A strong

predictor of outcome in patients with acute myocardial infarction and a sensitive

measure to compare thrombolytic regimens. A substudy of the international joint

efficacy comparison ofthrombolytics (INJECT) trial. J. Am. Coll. Cardiol., 26, 16571664.

60. Schroder, R. et al. (1994). Extent of early ST segment elevation resolution: A simple

but strong predictor of outcome in patients with acute myocardial infarction. J. Am.

Coll. Cardiol., 24, 384-391.

61. Rapilysin: Reteplase. (1998). Standard Information for Hospital Pharmacists.

Boehringer Mannheim.



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