File(s) not publicly available

The effect of high storage temperature on the stability and efficacy of lyophilized tenecteplase

journal contribution
posted on 21.06.2021, 22:42 authored by Emily Henkel, Rebecca Vella, Andrew FenningAndrew Fenning
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.

History

Volume

35

Issue

5

Start Page

501

End Page

507

Number of Pages

7

eISSN

1945-1938

ISSN

1049-023X

Location

United States

Publisher

Cambridge University Press

Language

eng

Peer Reviewed

Yes

Open Access

No

Acceptance Date

07/04/2020

Era Eligible

Yes

Medium

Print-Electronic

Journal

Prehospital and Disaster Medicine

Article Number

PII S1049023X20000928