Prediction of Human Distribution Volumes of Compounds in Various Elimination Phases Using Physiologically Based Pharmacokinetic Modeling and Experimental Pharmacokinetics in Animals.

Predicting the pharmacokinetics of compounds in humans is an important part of the drug development process. In this study, the plasma concentration profiles of 10 marketed compounds exhibiting two-phase elimination after intravenous administration in humans were evaluated in terms of distribution volumes just after intravenous administration (V 1), at steady state (V ss), and in the elimination phase (Vβ ) using physiologically based pharmacokinetic (PBPK) modeling implemented in a commercially available simulator (Simcyp). When developing human PBPK models, the insight gained from prior animal PBPK models based on nonclinical data informed the optimization of the lipophilicity input of the compounds and the selection of the appropriate mechanistic tissue partition methods. The accuracy of V 1, V ss, and Vβ values predicted that using human PBPK models developed in accordance with prior animal PBPK models was superior to using those predicted using conventional approaches, such as allometric scaling, especially for V 1 and Vβ By conventional approaches, the V 1 and Vβ values of 4-5 of 10 compounds were predicted within a 3-fold error of observed values, whereas V ss values for their majority were predicted as such. PBPK models predicted V 1, V ss, and Vβ values for almost all compounds within 3-fold errors, resulting in better predictions of plasma concentration profiles than allometric scaling. The distribution volumes predicted using human PBPK models based on prior animal PBPK modeling were more accurate than those predicted without reference to animal models. This study demonstrated that human PBPK models developed with consideration of animal PBPK models could accurately predict distribution volumes in various elimination phases.