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The Effect of High Storage Temperature on the Stability and Efficacy of Lyophilized Tenecteplase

Published online by Cambridge University Press:  20 July 2020

Emily Henkel Open the ORCID record for Emily Henkel [Opens in a new window] ,
Rebecca Vella  and
Andrew Fenning
Emily Henkel*
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
Rebecca Vella
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
Andrew Fenning
Affiliation:
Central Queensland University, School of Health, Medical and Applied Sciences, Rockhampton, Queensland, Australia
*
Correspondence: Emily Henkel, BSc (Hons) Central Queensland UniversitySchool of Health, Medical and Applied Sciences 554-700 Yaamba Road Rockhampton, Queensland4701Australia E-mail: emily.henkel@cqumail.com
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Abstract

Introduction:

Tenecteplase is a thrombolytic protein drug used by paramedics, emergency responders, and critical care medical personnel for the prehospital treatment of blood clotting diseases. Minimizing the time between symptom onset and the initiation of thrombolytic treatment is important for reducing mortality and improving patient outcomes. However, the structure of protein drug molecules makes them susceptible to physical and chemical degradation that could potentially result in considerable adverse effects. In locations that experience extreme temperatures, lyophilized tenecteplase transported in emergency service vehicles (ESVs) may be subjected to conditions that exceed the manufacturer’s recommendations, particularly when access to the ambulance station is limited.

Study Objective:

This study evaluated the impact of heat exposure (based on temperatures experienced in an emergency vehicle during summer in a regional Australian city) on the stability and efficacy of lyophilized tenecteplase.

Methods:

Vials containing 50mg lyophilized tenecteplase were stored at 4.0°C (39.2°F), 35.5°C (95.9°F), or 44.9°C (112.8°F) for a continuous period of eight hours prior to reconstitution. Stability and efficacy were determined through assessment of: optical clarity and pH; analyte concentration using UV spectrometry; percent protein monomer and single chain protein using size-exclusion chromatography; and in vitro bioactivity using whole blood clot weight and fibrin degradation product (D-dimer) development.

Results:

Heat treatment, particularly at 44.9°C, was found to have the greatest impact on tenecteplase solubility; the amount of protein monomer and single chain protein lost (suggesting structural vulnerability); and the capacity for clot lysis in the form of decreased D-dimer production. Meanwhile, storage at 4.0°C preserved tenecteplase stability and in vitro bioactivity.

Conclusion:

The findings indicate that, in its lyophilized form, even relatively short exposure to high temperature can negatively affect tenecteplase stability and pharmacological efficacy. It is therefore important that measures are implemented to ensure the storage temperature is kept below 30.0°C (86.0°F), as recommended by manufacturers, and that repeated refrigeration-heat cycling is avoided. This will ensure drug administration provides more replicable thrombolysis upon reaching critical care facilities.

Keywords

drug stabilitydrug storageEmergency Medical Servicesprehospital emergency caretenecteplase
Type
Original Research
Information
Prehospital and Disaster Medicine , Volume 35 , Issue 5 , October 2020 , pp. 501 - 507
Copyright
© World Association for Disaster and Emergency Medicine 2020

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References

Huynh, T, Birkhead, J, Huber, K, et al. The pre-hospital fibrinolysis experience in Europe and North America and implications for wider dissemination. JACC Cardiovasc Interv. 2011;4(8):877–883.Google ScholarPubMed
Thiebaut, AM, Gauberti, M, Ali, C, et al. The role of plasminogen activators in stroke treatment: Fibrinolysis and beyond. Lancet Neurol. 2018;17(12):1121–1132.CrossRefGoogle ScholarPubMed
Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet. 1999;354(9180):716–722.CrossRefGoogle Scholar
Guillermin, A, Yan, DJ, Perrier, A, Marti, C. Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: a systematic review and meta-analysis of randomized trials. Arch Med Sci. 2016;12(6):1181–1187.CrossRefGoogle ScholarPubMed
Boersma, E, Maas, ACP, Deckers, JW, Simoons, ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348(9030):771–775.CrossRefGoogle ScholarPubMed
Myers, RB. Prehospital management of acute myocardial infarction: electrocardiogram acquisition and interpretation, and thrombolysis by prehospital care providers. Can J Cardiol. 1998;14(10):1231–1240.Google ScholarPubMed
Morrison, LJ, Verbeek, R, McDonald, AC. Mortality and prehospital thrombolysis for acute myocardial infarction. JAMA. 2000;283(20):2686–2692.Google ScholarPubMed
Björklund, E, Stenestrand, U, Lindbäck, J, Svensson, L, Wallentin, L, Lindahl, B. Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mortality in ambulance-transported real-life patients with ST-elevation myocardial infarction. Eur Heart J. 2006;27(10):1146–1152.CrossRefGoogle ScholarPubMed
Welsh, RC, Travers, A, Senaratne, M, Williams, R, Armstrong, PW. Feasibility and applicability of paramedic-based prehospital fibrinolysis in a large North American center. Am Heart J. 2006;152(6):1007–1014.CrossRefGoogle Scholar
Gottwald, MD, Akers, LC, Liu, PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med. 1999;17(4):333–337.Google ScholarPubMed
McMullan, JT, Pinnawin, A, Jones, E, et al. The 60-day temperature-dependent degradation of midazolam and lorazepam in the prehospital environment. Prehosp Emerg Care. 2013;17(1):1–7.CrossRefGoogle ScholarPubMed
Vimalavathini, R, Gitanjali, B. Effect of temperature on the potency & pharmacological action of insulin. Indian J Med Res. 2009;130(2):166–169.Google ScholarPubMed
Alsenaidy, MA, Jain, NK, Kim, JH, Middaugh, CR, Volkin, DB. Protein comparability assessments and potential applicability of high throughput biophysical methods and data visualization tools to compare physical stability profiles. Front Pharmacol. 2014;5:1–19.CrossRefGoogle ScholarPubMed
Cui, Y, Cui, P, Chen, B, Li, S, Guan, H. Monoclonal antibodies: formulations of marketed products and recent advances in novel delivery system. Drug Dev Ind Pharm. 2017;43(4):519–530.Google ScholarPubMed
Kommanaboyina, B, Rhodes, CT. Trends in stability testing, with emphasis on stability during distribution and storage. Drug Dev Ind Pharm. 1999;25(7):857–868.CrossRefGoogle ScholarPubMed
Lentz, YK, Joyce, M, Lam, X. In vitro stability and compatibility of tenecteplase in central venous access devices. Hemodial Int. 2011;15(2):264–272.CrossRefGoogle ScholarPubMed
Stein, C. Medication storage temperatures in primary response vehicles. S Afr Med J. 2008;98(7):535–536.Google ScholarPubMed
Brown, LH, Krumperman, K, Fullagar, CJ. Out-of-hospital medication storage temperatures: a review of the literature and directions for the future. Prehosp Emerg Care. 2004;8(2):200–206.Google ScholarPubMed
Semba, CP, Weck, S, Razavi, MK, Tuomi, L, Patapoff, T. Tenecteplase: stability and bioactivity of thawed or diluted solutions used in peripheral thrombolysis. J Vasc Interv Radiol. 2003;14(4):475–479.CrossRefGoogle ScholarPubMed
Prasad, S, Kashyap, RS, Deopujari, JY, Purohit, HJ, Taori, GM, Daginawala, HF. Development of an in vitro model to study clot lysis activity of thrombolytic drugs. Thromb J. 2006;4:14.Google Scholar
Kasper, JC, Friess, W. The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eur J Pharm Biopharm. 2011;78(2):248–263.CrossRefGoogle ScholarPubMed
Jo, YH, Shin, WG, Lee, JY, et al. Evaluation of an intravenous preparation information system for improving the reconstitution and dilution process. Int J Med Inform. 2016;94:123–133.Google ScholarPubMed
Rosenberg, AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–E507.CrossRefGoogle Scholar
Rijken, DC. Relationships between structure and function of tissue-type plasminogen activator. Klin Wochenschr. 1988;66(12):33–39.Google ScholarPubMed
Jiang, H, Wu, SL, Karger, BL, Hancock, WS. Characterization of the glycosylation occupancy and the active site in the follow-on protein therapeutic: TNK-tissue plasminogen activator. Anal Chem. 2010;82(14):6154–6162.CrossRefGoogle ScholarPubMed
Loscalzo, J. Structural and kinetic comparison of recombinant human single- and two-chain tissue plasminogen activator. J Clin Invest. 1998;82(4):1391–1397.CrossRefGoogle Scholar
Baruah, DB, Dash, RN, Chaudhari, MR, Kadam, SS. Plasminogen activators: a comparison. Vascul Pharmacol. 2006;44(1):1–9.CrossRefGoogle ScholarPubMed
Tucker, KL, Sage, T, Gibbins, JM. Clot retraction. Methods Mol Biol. 2012;788:101–107.CrossRefGoogle ScholarPubMed
Sabovic, M, Lijnen, HR, Keber, D, Collen, D. Effect of retraction on the lysis of human clots with fibrin specific and non-fibrin specific plasminogen activators. Thromb Haemost. 1989;62(4):1083–1087.Google ScholarPubMed
López, M, Ojeda, A, Arocha-Piñango, CL. In vitro clot lysis: a comparative study of two methods. Thromb Res. 2000:97(2):85–87.CrossRefGoogle ScholarPubMed
Elnager, A, Abdullah, WZ, Hassan, R, et al. In vitro whole blood clot lysis for fibrinolytic activity study using D-dimer and confocal microscopy. Adv Hematol. 2014;2014:814684.CrossRefGoogle ScholarPubMed
Wakai, A, Gleeson, A, Winter, D. Role of fibrin D-dimer testing in emergency medicine. Emerg Med J. 2003;20(4):319–325.CrossRefGoogle ScholarPubMed
Brügger-Andersen, T, Hetland, Ø, Pönitz, V, Grundt, H, Nilsen, DWT. The effect of primary percutaneous coronary intervention as compared to tenecteplase on myeloperoxidase, pregnancy-associated plasma protein A, soluble fibrin and D-dimer in acute myocardial infarction. Thromb Res. 2007;119(4):415–421.CrossRefGoogle ScholarPubMed
Riley, RS, Gilbert, AR, Dalton, JB, Pai, S, McPherson, RA. Widely used types and clinical applications of D-dimer assay. Lab Med. 2016;47(2):90–102.Google ScholarPubMed
Lew, AS, Berberian, L, Cercek, B, Lee, S, Shah, PK, Ganz, W. Elevated serum D dimer: a degradation product of cross-linked fibrin (XDP) after intravenous streptokinase during acute myocardial infarction. J Am Coll Cardiol. 1986;7(6):1320–1324.CrossRefGoogle Scholar
Melzer, C, Richter, C, Rogalla, P, et al. Tenecteplase for the treatment of massive and sub-massive pulmonary embolism. J Thromb Thrombolysis. 2004;18(1):47–50.CrossRefGoogle Scholar
INNOVANCE® D-Dimer (package insert). Marburg (Germany): Siemens Healthcare Diagnostics Products GmbH; 2017.Google Scholar
Valenzuela, TD, Criss, EA, Hammargren, WM, et al. Thermal stability of prehospital medications. Ann Emerg Med. 1989;18(2):173–176.CrossRefGoogle ScholarPubMed
Johansen, RB, Schafer, NC, Brown, PI. Effect of extreme temperatures on drugs for prehospital ACLS. Am J Emerg Med. 1993;11(5):450–452.CrossRefGoogle ScholarPubMed
Gill, MA, Kislik, AZ, Gore, L, Chandna, A. Stability of advanced life support drugs in the field. Am J Health Syst Pharm. 2004;61(6):597–602.CrossRefGoogle ScholarPubMed
Gammon, DL, Su, S, Jordan, J, et al. Alteration in prehospital drug concentration after thermal exposure. Am J Emerg Med. 2008;26(5):566–573.CrossRefGoogle ScholarPubMed
De Winter, S, Vanbrabant, P, Tuong Vi, NT, et al. Impact of temperature exposure on stability of drugs in a real-world out-of-hospital setting. Ann Emerg Med. 2013;62(4):380–387.CrossRefGoogle Scholar
Brown, LH, Wojcik, SM, Bailey, LC, Tran, CD. Can stock rotation effectively mitigate EMS medication exposure to excessive heat and cold? Am J Emerg Med. 2006;24(1):14–18.CrossRefGoogle Scholar
Allegra, JR, Brennan, J, Lanier, V, Lavery, R, MacKenzie, B. Storage temperatures of out-of-hospital medications. Acad Emerg Med. 1999;6(11):1098–1103.CrossRefGoogle ScholarPubMed
DuBois, WC. Drug storage temperatures in rescue vehicles. J Emerg Med. 2000;18(3):345–348.CrossRefGoogle ScholarPubMed
Allegra, J, Brennan, J, Fields, L, et al. Monitoring the storage temperature of ambulance medications with time-temperature indicators. Hosp Pharm. 2000;35(3):246–250.CrossRefGoogle Scholar
García-Manzano, A, González-Llaven, J, Lemini, C, Rubio-Póo, C. Standardization of rat blood clotting tests with reagents used for humans. Proc West Pharmacol Soc. 2001;44:153–155.Google ScholarPubMed