Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

Abstract

Objective-Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R( +) and S(-) terodiline enantiomers. (443 (33) and 42 (17) ms'12, paired t tests, P < 0-002 and P < 0 01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) Ms112 for QTc and 42 (13 to 70) ms'12 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0-77, P < 0-006, QTd: r = 0*68, P < 0.025) and with plasma concentrations of both terodiline enantiomers.Conclusions-Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction. (Br HeartJ7 1995;74:53-56)

Enantiomeric drug development: Issues, considerations, and regulatory requirements

“…6,13,14 The developability of the terodiline racemate would be viewed differently if only an enantioselective investigation into its toxicity pro®le had been undertaken earlier because, recently, it was shown that although both enantiomers of terodoline are equipotent in their therapeutic bene®ts, the cardiac polarization (prolongation of QTc interval and QRS duration) and proarrhythmic properties were due to the R()-enantiomer. 15 Had this information been available earlier during the clinical development of terodiline, the development of the S(-)-enantiomer instead of the racemate would have been favored.…”

Efficacy and Cardiac Safety of Propiverine in Elderly Patients &ndash; A Double&ndash;Blind, Placebo&ndash;Controlled Clinical Study

“…The calcium antagonist terodiline has been associated with cardiovascular events, including cardiac arrhythmias with prolonged Q–T intervals [7, 8, 9, 10]. Therefore, in view of the calcium–antagonistic properties of propiverine, the thorough investigation of possible arrhythmogenic effects of propiverine was initiated under a therapeutic dosage regime.…”

“…These cardiac arrhythmias were probably caused by the concentration–related prolongation of the frequency–corrected Q–T (Q–Tc) interval [10]. However, this phenomenon has not been reported for anticholinergic drugs, such as oxybutynin [11].…”

The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment

“…Terodiline. Terodiline concentrations ranging from 32.9 nM up to the clinically relevant level (Thomas et al, 1995) of 120 nM caused statistically significant increases in the mean QT RR1000 of 9 to 12 ms. As in the case of cisapride, the dose-response curve was bell-shaped, with the greatest mean QT prolongation occurring at the third free drug concentration level achieved of 32.9 nM.…”