TY - JOUR T1 - The antitussive pentoxyverine (POV) has a low proarrhythmic risk based on an <em>in vitro</em> and <em>in vivo </em>integrated risk assessment JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P581 AU - Thomas Weiser AU - Brian Guth AU - Georg Rast AU - Michael Markert AU - Holger Fuchs AU - André Liesener Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P581.abstract N2 - Our study investigated POV-induced effects in various preclinical models, since potency for blocking hERG channels alone is not sufficient to assess its proarrhythmic potential.POV inhibited hERG channels with an IC50 of 13.8 uM using a manual patch clamp assay. Action potential duration (APD) in the guinea pig papillary muscle was prolonged minimally by ∼3% at 1 uM but then was reduced by ∼20% at 10 uM. Thus, the in vitro data suggest that concentrations that could cause hERG-mediated APD prolongation are associated with other effects that lead to a substantial APD shortening.The effect of POV on the QT-interval was investigated in anaesthetized Beagle dogs using intravenous infusion of 1, 3, 10 and finally 30 mg/kg using an escalating dose design. Heart rate (HR), blood pressure (BP), max. value of the first derivative of the left ventricular pressure (LVdP/dtmax), as well as the ECG were measured and related to plasma drug levels.The step-wise infusions lead to POV plasma concentrations of 0.63, 2.1, 12.2 and 108 uM at the end of each dose step. HR was held constant with pacing. BP was reduced starting at POV concentrations &gt;12.2 uM. Only a slight (∼5%) prolongation of the QT-interval was observed at 12 uM but higher concentrations led to an exposure-dependent and ultimately fatal drop in BP and LVdP/dtmax.Our data show that POV does not affect the QT interval relevantly up to the highest tolerable concentration in the in vivo model used. Based on all available data, both in vitro and in vivo, the proarrhythmic risk based on QT prolongation with therapeutic doses of POV (mean Cmax in man @ 30 mg appr. 0.14 uM) is considered very low. ER -