Application of fixed exponent 0.75 to the prediction of human drug clearance: an inaccurate and misleading concept.
Considering the controversy surrounding the exponent of 0.75 for the prediction of human drug clearance and lack of any systematic evaluation of the aforementioned proposal, the objective of this study was to determine whether the exponent 0.75 is indeed the most suitable exponent for the prediction of human drug clearance as compared to allometric scaling using the rule of exponents (ROE). Three methods were used to predict human drug clearance. Besides evaluating the exponent of 0.75, an arbitrarily selected exponent of 0.65 was also tested. ROE was also used to predict human drug clearance, and predicted values by all three methods were compared with observed human drug clearance. The results indicate that the exponent 0.75 is not the best approach for the prediction of human drug clearance. Both exponents 0.75 and 0.65 predicted human drug clearance with uncertainty, although on average the prediction of human drug clearance by 0.65 was better than the exponent 0.75. ROE provided far more accurate prediction of human drug clearance than either of the exponents. Although exponent 0.75 occasionally provided a good prediction of human drug clearance for a given drug for a given species, overall, the method is highly erratic and unreliable.
Office of Blood Review & Research, Center for Biologic Evaluation and Research, Food & Drug Administration, 1451 Rockville Pike, MD 20852, USA. iftekhar.mahmood@fda.hhs.gov
Iftekhar
I
Mahmood
D000818:Animals; D001481:Basal Metabolism / Q000502:physiology; D049628:Body Size / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D006801:Humans; D008657:Metabolic Clearance Rate / Q000502:physiology*; D008954:Models, Biological; D013045:Species Specificity