H. Kasai, K. Ueno, M. Kusumoto
Mar 1, 1999
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Quality indicators
Journal
European Journal of Clinical Pharmacology
Abstract
Pirmenol is a class Ia antiarrhythmic agent and is reported to be eective for premature ventricular contractions [1±3]. Pirmenol is mainly eliminated by hepatic metabolism, although more than 23% of the dose is excreted in urine in an unchanged form [4]. However, at present only limited information is available, based on small-scale pharmacokinetic studies. Thus, we studied the population pharmacokinetics of pirmenol in patients and investigated the eects of demographic or clinical factors on the pharmacokinetic parameters. Data were obtained from 90 subjects during phase 1 or 2 clinical trials [5±7] and post marketing study. Thirty-eight of the subjects were patients at Maizuru Kyosai Hospital and they received pirmenol in a post marketing study; only one concentration was measured per patient (Table 1). All subjects provided informed consent before enrolling onto the study, which was approved by the institutional ethics committee of Maizuru Kyosai Hospital. Plasma pirmenol concentrations were determined by HPLC [8]. No subjects received rifampicin, which enhances pirmenol elimination because of the induction of hepatic drug-metabolizing enzymes [9]. The time course of pirmenol was described using a one-compartment open model without absorption because the absorption phase could not be clearly seen. Bioavailability was assumed to be complete in the normal state. All data from all subjects were ®tted simultaneously with NONMEM (Version IV) [10]. The eects of gender, body weight, age and creatinine clearance on total clearance (CL), volume of distribution (Vd) and relative bioavailability were investigated. The signi®cance of those factors was tested by a likelihood ratio test with a signi®cance level of P < 0.05. The ®nal population pharmacokinetic model with signi®cant covariates was as follows: CL l hÿ1 kgÿ1 0:240 1ÿ0:00563 age (years); Vd l kgÿ1 2:06. No statistically signi®cant eect on either volume of distribution or relative bioavailability was found. The interindividual variations in CL and Vd were 62.0% and 27.0%, respectively. The residual variation was 32.1%. In this study, it was shown that CL was negatively correlated to age, which might be caused by hepatic and/ or renal dysfunction. The relationships between each subject's age and CL estimated by the Bayesian method is shown in Fig. 1. Two regression lines using data from Eur J Clin Pharmacol (1999) 55: 77±78 Ó Springer-Verlag 1999