Pirmenol kinetics and effective oral dose

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Abstract
The oral form of pirmenol [an antiarrhythmic] had not been administered to man. Pirmenol was given by mouth to 8 patients with chronic, stable premature ventricular beats (PV) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol followed by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150-250 mg induced at least 90% suppression of PVB 18 of the 19 times they were administered during both protocols. During the double-blind experiment, a single oral dose of pirmenol suppressed 95 .+-. 8% PV/h (mean .+-. SD) for 3 consecutive h, while placebo suppressed 4 .+-. 42% PVB/h (P < 0.01). A .gtoreq. 90% reduction in PVB persisted for a median of 6 h (range 1-8 h). The range of plasma pirmenonl concentrations associated with an at least 90% reduction in PVB was 0.7-2.0 .mu.g/ml. Median half-life (t1/2) was 9.3 h (range 6.0-12.4), protein binding 86.6 .+-. 2.4% and bioavailability 82.6 .+-. 23.6%. At peak drug level there was lengthening of the QTc interval (0.036 s, P < 0.05) but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVB, had a relatively long t1/2 and was minimally toxic.