Population pharmacokinetic parameters in patients treated with oral mexiletine.
A new data analysis approach, NON-MEM, proposed by Sheiner and Beal, has been employed to estimate the population pharmacokinetic parameters of oral mexiletine in patients treated for arrhythmias. 452 serum concentration measurements in 58 patients were available for analysis. 27 patients had congestive heart failure and 8 had abnormal liver function tests at the time of the study. The population averages of the pharmacokinetic parameters and their interindividual variability were: oral total body clearance (Cl) 0.38 l/h/kg +/- 43% (C.V.), apparent volume of distribution (Vd) 5.3 l/kg +/- 40%, absorption rate constant 3.1 h-1 +/- 205%, absorption time-lag 0.3 h. Congestive heart failure and sex did not show a significant effect on Cl and Vd; the number of patients with severe liver function impairment was too small for a definite conclusion. Normalizing Cl and Vd for body weight significantly decreased their interindividual variability. Based on these results, a dosage regimen is recommended which is expected to produce a "therapeutic" serum concentration (0.8-2 mg/l) in over 60% of patients. Because of its unique features, which allow estimation of pharmacokinetic parameters and their variability from fragmentary patient data, the NONMEM system has great potential applicability to clinical pharmacokinetic studies.
D000368:Aged; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008801:Mexiletine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D011437:Propylamines / Q000378:metabolism*
D011437:Propylamines; D008801:Mexiletine