title: Allometric pharmacokinetic scaling: towards the prediction of human oral pharmacokinetics.
abstract: OBJECTIVE
  To evaluate (1) allometric scaling of systemic clearance (CL) using 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 x W(biv)) using unbound plasma concentration for eight Parke-Davis compounds and 29 drugs from literature sources. When the exponent b(iv) was higher than 0.85, BRW was incorporated into the allometric relationship (CLu*BRW = a x W(biv)). This approach was also applied to the prediction of CLu/F for 10 Parke-Davis compounds. Human oral t1/2, Cmax, AUC, and bioavailability were estimated based on allometrically predicted pharmacokinetic (PK) parameters.
  
  
  RESULTS
  Human CL and CL/F were more accurately estimated using unbound drug concentration and the prediction was further improved when BRW was incorporated into the allometric relationship. For Parke-Davis compounds, the predicted human CL and CL/F were within 50-200% and 50-220% of the actual values, 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, suggesting that human oral PK parameters of those drugs could be reasonably predicted from animal data.
  
  
  CONCLUSIONS
  Results from the retrospective analysis indicate that allometric scaling of free concentration could be applied to orally administered drugs to gain knowledge of drug disposition in man, and to help decision-making at early stages of drug development.
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. rose.feng@wl.com
authors.forename: M R
authors.initials: MR
authors.lastname: Feng
authors.forename: X
authors.initials: X
authors.lastname: Lou
authors.forename: R R
authors.initials: RR
authors.lastname: Brown
authors.forename: A
authors.initials: A
authors.lastname: Hutchaleelaha
mesh_terms: D019540:Area Under Curve; D006801:Humans; D009055:Mouth / Q000378:metabolism*; D010599:Pharmacokinetics; D012189:Retrospective Studies