Determination of the Number of Tissue Groups of Kinetically Distinct Transit Time in Whole-Body Physiologically Based Pharmacokinetic (PBPK) Models I: Theoretical Consideration of Bottom-Up Approach of Lumping Tissues in Whole-Body PBPK

AbstractMinimal physiologically based pharmacokinetic (mPBPK) models, consisting of system-specific (e.g., tissue volume and blood flow) and drug-related (e.g., tissue-to-plasma partition coefficient) parameters, are practically useful for pharmacokinetic analyses. However, biopharmaceutical principles were not clear on how peripheral tissues, adopted in whole-body physiologically based pharmacokinetic (WB-PBPK) models, could be kinetically consolidated into one or two tissue groups in the mPBPK models. In this theoretical examination, we studied the relationship between the progressive tissue lumping in the direction from the longest mean transit time (MTTmax) to the shorter one(s) and the slopes of the terminal (λter)/distributional phases, assuming tissues with comparableMTTs are kinetically combined. The appropriateness of lumping was ascertained by evaluating the impact of difference in tissueMTTs during the lumping on the analytical solution of WB-PBPK models. We found that the ratio ofMTTmax to the mean residence time in the body, viz.,Kdet, is related to the change inλter by the progressive lumping and can serve as an index for the robustness ofλter. Calculations with two extreme cases revealed that, for caffeine atKdet <  0.03, the change inλter was minimal even when all peripheral tissues were collectively lumped, whereas for artesunic acid atKdet >  50, the tissue ofMTTmax could not be kinetically combined even with the tissue having the second-lo...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research