Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study

Pharmacokinetic parameters (clearance, CL, volume of distribution in the ce ntral compartment, Vdc, and elimination half-life, t(1/2 beta)) predicted b y an empirical allometric approach have been compared with parameters predi cted from plasma concentrations calculated by use of the pharmacokinetic co nstants A, B, alpha and beta, where A and B are the intercepts on the Y axi s of the plot of plasma concentration against time and alpha and beta are t he rate constants, both pairs of constants being for the distribution and e limination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, pr ocaterol, moxalactam and ciprofloxacin were scaled from animal data obtaine d from the literature. Three methods were used to generate plots for the pr ediction of clearance in man: dependence of clearance on body weight (simpl e allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the dru gs were predicted in man by use of A, B, alpha and beta obtained from anima l data. The predicted plasma concentrations were then used to calculate CL, Vd(C) and t(1/2 beta). The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate th at simple allometry did not predict clearance satisfactorily for actisomide , troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these f our drugs. Except for troglitazone, Vd(C) and t(1/2 beta) predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, Vd(C) and t(1/2 beta) predicted by use of pharmacok inetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did th e pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in inter preting plasma concentrations predicted for a drug in man by use of pharmac okinetic constants obtained in animals.