Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog

1. Torsades de pointes (TDP) is a potentially fatal ventricular tachycardia associated with increases in QT interval and monophasic action potential d uration (MAPD). TDP is a side-effect that has led to withdrawal of several drugs from the market (e.g. terfenadine and terodiline). 2. The potential of compounds to cause TDP was evaluated by monitoring thei r effects on MAPD in dog. Four compounds known to increase QT interval and cause TDP were investigated: terfenadine, terodiline, cisapride and E4031. On the basis that only free drug in the systemic circulation will elicit a pharmacological response target, free concentrations in plasma were selecte d to mimic the free drug exposures in man. Infusion regimens were designed that rapidly achieved and maintained target-free concentrations of these dr ugs in plasma and data on the relationship between free concentration and c hanges in MAPD were obtained for these compounds. 3. These data indicate that the free ED50 in plasma for terfenadine (1.9 nM ), terodiline (76 nM), cisapride (11 nM) and E4031 (1.9 nM) closely correla te with the free concentration in man causing QT effects. For compounds tha t have shown TDP in the clinic (terfenadine, terodiline, cisapride) there i s little differentiation between the dog ED50 and the efficacious free plas ma concentrations in man (<10-fold) reflecting their limited safety margins . These data underline the need to maximize the therapeutic ratio with resp ect to TDP in potential development candidates and the importance of using free drug concentrations in pharmacokinetic/pharmacodynamic studies.