Interspecies scaling for the prediction of drug clearance in children: application of maximum lifespan potential and an empirical correction factor.
OBJECTIVE
Interspecies pharmacokinetic scaling is widely used to predict pharmacokinetic parameters in adult humans but has not been used for the prediction of pharmacokinetic parameters in children. The current study was undertaken to evaluate whether or not drug clearance in children from adult rat, dog and human clearance values could be predicted allometrically.


METHODS
Four methods (simple allometry, maximum lifespan potential [MLP], MLP with an empirical correction factor and a fixed exponent of 0.75 in association with adult data) were used for the prediction of drug clearance in children. The first three methods included adult animal (rat and dog) data and human data, whereas the fixed exponent of 0.75 included only adult human data.


RESULTS
The results of this study indicated that simple allometry would systematically overpredict drug clearance in children, whereas application of MLP would underpredict drug clearance in children. Therefore, an empirical correction factor was introduced into MLP, which substantially improved the prediction of drug clearance in children. Prediction based on a fixed exponent of 0.75 and adult human clearance was highly erratic and inferior to the prediction of drug clearance in children from MLP or MLP with an empirical correction factor.


CONCLUSIONS
Overall, the results of the study indicated that interspecies scaling using adult rat, dog and human clearance values could be useful to predict drug clearance in children in different age groups.
Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA. iftekhar.mahmood@fda.hhs.gov
Iftekhar
I
Mahmood
D000293:Adolescent; D000367:Age Factors; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004285:Dogs; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008657:Metabolic Clearance Rate; D008722:Methods; D008962:Models, Theoretical; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D051381:Rats; D013045:Species Specificity