W. Weber(1) , L. Harnisch(1) , M. Zimmer(1) , P. Crause(2) , B. Katgely(1)
Clinical Research(1) and Department of Biochemistry(2)
Hoechst AG, Frankfurt/Main, Germany
''First dose in man'' - studies should always be designed on the basis of preclinical data. Allometric scaling is often used to extrapolate the pharmacokinetics of animals to man. In a conventional approach, typical pharmacokinetic parameters like clearance (CL) and volume of distribution (Vd) are calculated for at least three different species. Then in a further step, these mean parameters are used to determine the coefficients of the allometric equation.
Often the data measured in an individual animal is sparse and imbalanced. In such situations, it has been shown that the use of a nonlinear mixed effect model (NONMEM) - as a single step approach - is superior to the conventional two-step-method. Both coefficients in the allometric equation for CL and Vd are determined directly from the pooled data of all animals. Thus a common pharmacokinetic model for all mammals is obtained. As expected, body weight ranging from 0.1 kg rat to 20 kg dog was found to be the most reliable covariate for the prediction of CL as well as Vd.
Sex differences in the metabolic behavior in rats were observed in the CL values of our analysis. The calculated mean CL was 2.5 fold higher in male than in female rats. Liver enzyme induction in rats caused by male sex hormones was described frequently in the past. To rule out the influence of this induction, only the data of female rats were pooled with data from dogs and monkeys and subjected to the analysis.
Subsequently the extrapolation of PK data from animal to man was performed. It was on the basis of this information that the "First dose in man" study was designed. In the meantime the results of several phase I studies have confirmed the predictions in regard to Vd. However, the predictions in regard to CL were less successful. In contrast to the three species where extensive metabolism was observed in humans there was only minor metabolism, if at all. 80% of the unchanged drug were renally eliminated in man, only 20% were excreted in the urine of rats.
Literature:
1. Tse FLS (1998) Nonclinical Pharmacokinetic Studies. In: Pharmacokinetics, ed. Welling PG and Tse FLS, Marcel Dekker, New York and Basel, p. 163
2. Sheiner LB, Ludden TM (1992) Population Pharmacokinetics/dynamics. Anu. Rev. Pharmacol. Toxicol. 32: 185-209
3. C. Efthymiopoulos, V. Cosson, A. Beye: The use of NONMEM in the interspecies allometric scaling. Second meeting of PAGE, London, June 1994