IDENTIFICATION OF PATIENTS WITH IMPAIRED HEPATIC DRUG-METABOLISM USING A LIMITED SAMPLING PROCEDURE FOR ESTIMATION OF PHENAZONE (ANTIPYRINE) PHARMACOKINETIC PARAMETERS

Phenazone (antipyrine) 1g was given by short intravenous infusion to 62 study participants (10 healthy drug-free volunteers and 52 patients with chronic liver disease). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of phenazone. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 30 patients. When combined with 1 plasma drug concentration from members of the second group, these led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 32 individuals. Total clearance computed by Bayesian estimation was compared with maximal likelihood estimation of this parameter, the classical procedure. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean error was 0.0477 L/h. The precision of the prediction of this parameter (0.155 L/h) remained lower than the interindividual standard deviation (0.765 L/h). This procedure enables the estimation of individual pharmacokinetic parameters for phenazone. In this study. numerous laboratory tests were performed. A highly significant correlation (p < 0.001) was found between phenazone clearance and the prothrombin time, albumin, gamma-globulin, factor V. antithrombin III, fibrinogen and total bilirubin. Discriminant analysis determined that protein, alkaline phosphatase, creatininaemia and gamma-globulin had more significant discriminating power and gave better prognostic results than those seen with the Child-Pugh test.