| Autor: |
L, Bergenholm, J, Parkinson, J, Mettetal, N D, Evans, M J, Chappell, T, Collins |
| Rok vydání: |
2016 |
| Předmět: |
|
| Zdroj: |
British journal of pharmacology. 174(19) |
| ISSN: |
1476-5381 |
| Popis: |
Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro NaSmall changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
Plný text