TOLERABILITY OF INCREASING SINGLE ORAL DOSES OF CLENTIAZEM IN HEALTHY-VOLUNTEERS

In a double-blind phase I study, healthy male volunteers were randomly assigned to receive clentiazem, a benzothiazepine calcium channel blocker (n = 24), or placebo (n = 3). Clentiazem was administered in increasing single oral doses of 0, 20, 40, 60, 80, 100 and 120mg, at weekly intervals. There was a significant increase in PR interval with clentiazem doses of greater-than-or-equal-to 80mg, while all other vital signs (VS) and ECG parameters remained unchanged. All parameters, with the exception of the PR interval, showed a significant response over time with the 0mg dose. A weak (r = 0.3183) but significant (p < 0.05) correlation was observed between mean maximum clentiazem plasma concentrations and PR interval. Seven of 21 volunteers receiving active doses of clentiazem experienced second degree atrioventricular (AV) block leading to discontinuation of treatment compared with 1 of 3 placebo recipients and 1 volunteer who received the 0mg dose. 38 adverse events rated as probably or possibly related to clentiazem were reported; the most commonly reported events were mild/moderate headache (n = 15), mild fatigue (8) and mild dizziness (3). No clinically significant changes in laboratory tests were noted with any clentiazem dose. In conclusion, clentiazem did not cause any deleterious changes in VS or laboratory tests in healthy volunteers. However, there was a dose-dependent lengthening of the PR interval which may, in turn, lead to an increased risk of AV block.