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Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke

 Jinju Guk  ;  Dongwoo Chae  ;  Hankil Son  ;  Joonsang Yoo  ;  Ji Hoe Heo  ;  Kyungsoo Park 
 British Journal of Clinical Pharmacology, Vol.84(11) : 2586-2599, 2018 
Journal Title
 British Journal of Clinical Pharmacology 
Issue Date
acute ischaemic stroke ; item response theory ; model-based benefit-risk analysis ; pharmacometrics ; recombinant t-PA
AIMS: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome. METHODS: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). RESULTS: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2-3 fold higher than with MCA stroke. CONCLUSIONS: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
박경수(Park, Kyungsoo) ORCID logo https://orcid.org/0000-0002-6972-1143
채동우(Chae, Dong Woo) ORCID logo https://orcid.org/0000-0002-7675-3821
허지회(Heo, Ji Hoe) ORCID logo https://orcid.org/0000-0001-9898-3321
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