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The effect of high storage temperature on the stability and efficacy of lyophilized tenecteplase
journal contribution
posted on 2021-06-21, 22:42 authored by Emily Henkel, Rebecca VellaRebecca Vella, Andrew FenningAndrew FenningIntroduction: 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
35Issue
5Start Page
501End Page
507Number of Pages
7eISSN
1945-1938ISSN
1049-023XLocation
United StatesPublisher
Cambridge University PressPublisher DOI
Language
engPeer Reviewed
- Yes
Open Access
- No
Acceptance Date
2020-04-07Era Eligible
- Yes
Medium
Print-ElectronicJournal
Prehospital and Disaster MedicineArticle Number
PII S1049023X20000928Usage metrics
Categories
Keywords
Drug stabilityDrug storageEmergency medical servicesPrehospital emergency careTenecteplaseAcute myocardial infarctionDiode-array detectionDithiothreitolEmergency service vehicleFibrinogen equivalent unitsHigh-performance liquid chromatographyMyocardial infarctionPulmonary embolismSodium dodecyl sulfateAnalytical Chemistry not elsewhere classifiedPharmacology and Pharmaceutical Sciences not elsewhere classifiedEmergency Medicine