Pharmacokinetic and pharmacodynamic evaluation of pirmenol enantiomers.

Abstract

Pirmenol is a chiral compound being developed in the racemic form as an antiarrhythmic agent. Pharmacokinetics and pharmacodynamics of pirmenol were studied in a dog model of ventricular arrhythmia and in patients with premature ventricular contractions (PVCs) to determine if any advantage exists for the use of either enantiomer over the racemate. Reduction in frequency of PVCs was determined following intravenous administration of 5 mg/kg pirmenol racemate (n = 5), (+)-pirmenol (n = 4), or ($-$)-pirmenol (n = 4) to mongrel dogs with induced ventricular arrhythmia by coronary artery ligation. Electrocardiographic signals and blood samples were obtained serially over 4 hours. Pharmacokinetics of pirmenol enantiomers and pharmacodynamics of pirmenol racemate were also investigated in twelve patients with PVCs following repeated oral administration of racemic pirmenol at 100 mg and 200 mg every 12 hours. Ambulatory electrocardiographic (Holter) monitoring was performed and serial blood samples were collected after the seventh dose at each dose level. In both studies (dog and human), pirmenol enantiomer concentrations in plasma were determined using a stereospecific liquid chromatographic assay and protein binding was assessed using equilibrium dialysis. Pharmacokinetic differences between unbound pirmenol enantiomers are minimal in the dog. Higher concentrations of total ($-$)-pirmenol in plasma are mostly a result of more extensive protein binding in dogs as compared to (+)-pirmenol. In patients, ($-$)-pirmenol is also more highly bound in plasma than is (+)-pirmenol. However, similar plasma enantiomer concentrations are observed for total pirmenol in patients since the more rapidly cleared unbound ($-$)-pirmenol is also more extensively bound to plasma proteins. Based on the dog model of induced ventricular arrhythmia, pirmenol enantiomers are equally effective in PVC suppression. Therefore, equivalent unbound plasma concentrations of separate enantiomers or racemate should result in an equivalent antiarrhythmic effect. Percent reduction in PVCs can be correlated with plasma pirmenol concentrations in a sigmoid-type relationship in both dogs and humans. Both species show a large variability in antiarrhythmic response to pirmenol. Higher concentrations were required for PVC suppression in the acute model of arrhythmia in the dog than for patients with PVCs; on average, pharmacodynamic parameters for pirmenol racemate differed by less than 5-fold between species. Based on pharmacokinetic data alone, there does not appear to be an advantage for development of either enantiomer over the pirmenol racemate. Although pharmacodynamic data of pirmenol enantiomers are similar in dogs, it is uncertain whether or not pirmenol enantiomers will have similar dynamic activities in humans, since in the absence of regulatory approval to administer individual enantiomers, only racemate has been studied to date.