Authors: Jochen Zisowsky Eliane Fuseau Shirin Bruderer Andreas Krause Jasper Dingemanse
Publish Date: 2014/01/24
Volume: 70, Issue: 4, Pages: 409-419
Abstract
This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage aSAH and the impact of collecting data in an intensive care unit ICU setting Factors influencing data quality analysis and interpretation are provided with recommendations for future clinical studies in ICU settingsCONSCIOUS2 was a phase III study involving 1157 patients with aSAH Secured by surgical clipping patients were infused with clazosentan or placebo for up to 14 days postaSAH Clazosentan exposure relationships with vital signs QT intervals and AST/ALT values as well as efficacy and safety endpoints were characterised using population PK/PD and logistic regression modelsClazosentan clearance was influenced by age sex Asian origin and disease status at baseline and increased with time Volume of distribution showed a sex difference Exposure had no relationship with any efficacy endpoint or ALT/AST values but was related to the increasing probability of lung complications Blood pressure decreased proportionally to clazosentan concentrations and the presence of clazosentan was associated with QT interval increases Implausible values in the concentration data reflect the specific ICU challenges possibly arising from PK sampling from the infusion arm or haemodilutionPopulation PK/PD modelling of CONCIOUS2 data provided clinically relevant knowledge about various effects of clazosentan in the aSAH patient population in a real clinical setting The quality of data and analyses could be improved by the collection of additional data and stricter training of study personnel Differences in clinical practice between sites and geographical regions are more challenging to overcomeActelion Pharmaceuticals Ltd provided funding for this clinical trial and for the work conducted by Eliane Fuseau EMF Consulting Jochen Zisowsky Shirin Bruderer Andreas Krause and Jasper Dingemanse are current employees and shareholders of Actelion Pharmaceuticals Ltd
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