Constantin Efthymiopoulos, PhD, Valérie Cosson, Pharm D, Alan Bye, PhD
Clinical Pharmacokinetics Department, Glaxo Research and Development Limited, Greenford, UK
Interspecies scaling of the pharmacokinetic parameters (P) is usually done using allometric equations as P= aWb, relating P to body weight (W). The coefficient (a) and exponent (b) of the allometric equation are determined by linear regression of the logarithmically transformed P and W values and correspond to the intercept and the slope of the regression, respectively. This can be viewed as a “two-stage” approach, where the pharmacokinetic parameters must be determined in each species first and then to perform the regression. A drawback of this approach (apart from being lengthy) is that very often the data available in a species are not sufficient for the pharmacokinetic parameters to be determined with a reasonable degree of precision.
We used NONMEM to perform interspecies pharmacokinetic scaling in one step. Both the coefficient and exponent in the allometric equation of the relevant pharmacokinetic parameters were determined directly from the individual data in each species. The body weight of each species was used as the covariate to model the variability in the typical values of eg. Clearance and Volume of distribution. Simulated and real data sets were used to evaluate the performance of the new approach in a number of cases (ie. when species differences in pharmacokinetics were present and absent and in data-poor and data-rich situations). The results of NONMEM were comparable to those obtained when the classic “two-stage” approach was used.
Reference: PAGE 3 (1994) Abstr 872 [www.page-meeting.org/?abstract=872]
Poster: oral presentation