Allometric pharmacokinetic scaling: Towards the prediction of human oral pharmacokinetics

Purpose. To evaluate (1) allometric scaling of systemic clearance (CL) usin g unbound drug concentration, (2) the potential usage of brain weight (BRW) correction in allometric scaling of both CL and oral clearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a . W-biv) usi ng unbound plasma concentration for eight Parke-Davis compounds and 29 drug s from literature sources. When the exponent bi, was higher than 0.85, BRW was incorporated into the allometric relationship (CLu*BRW = a.W-biv). This approach was also applied to the prediction of CLu/F for 10 Parke-Davis co mpounds. Human oral t1/2, Cmax, AUC, and bioavailability were estimated bas ed on allometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated using unbound dru g concentration and the prediction was further improved when BRW was incorp orated into the allometric relationship. For Parke-Davis compounds, the pre dicted human CL and CL/F were within 50-200% and 50-220% of the actual valu es, respectively The estimated human oral t1/2 Cmax, and AUC were within 82 -220%, 56-240%, and 73-190% of the actual values for all 7 compounds, sugge sting that human oral PK parameters of those drugs could be reasonably pred icted from animal data. Conclusions. Results from the retrospective analysis indicate that allometr ic scaling of free concentration could be applied to orally administered dr ugs to gain knowledge of drug disposition in man, and to help decision-maki ng at early stages of drug development.