Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib

Abstract

AUC, area under the concentration-time curve; AUC 0-24 , area under the concentration-time curve from time 0 to 24h postdose; AUC 0-168 , area under the concentration-time curve from time 0 to 168h postdose; AUC ss , area under the concentration-time curve at from time 0 to 24h postdose at steady-state; AUC 0-inf , area under the concentration-time curve from time 0 to infinity; Cl, clearance; Cl int , intrinsic clearance; C max , maximum concentration; t max , time to maximum concentration; C ss , mean plasma concentration level at steady state; C sol , solubility in gastrointestinal tract segment ; C sol_stomach , solubility in stomach compartment; C sol_IF , solubility in intestinal compartment; C p , concentration in plasma; C liv , concentration in liver; f u , fraction unbound; GIT, gastrointestinal tract; ke, elimination rate constant; ka, absorption rate constant; Kt, small intestinal transit rate constant; Kt.stom, gastric emptying rate constant; Kt.colon, colonic excretion rate constant; PBPK, physiologically based pharmacokinetic; PGF, permeation gradient factor; PK, pharmacokinetics; Q h , blood flow rate; SI, small intestinal segment; Vd, volume of distribution; V/F, apparent volume of distribution after oral dose;

Canadian Content in the Pages of Drug Metabolism and Disposition: A Comprehensive Historical Analysis

“…Other UBC scientists have studied the metabolism of acetylhydrazine, a hepatotoxic isoniazid metabolite (Wright and Timbrell, 1978), the metabolism of biologically active vitamin D 3 by mouse and human liver CYP3A enzymes (Deb et al, 2012), the presence of active UDPglucuronosyltransferase 1A (UGT1A) proteins in the mouse blastocyst (Collier et al, 2014), and the ontogeny and variability of human hepatic NAD(P)H-quinone oxidoreductase 1 (NQO1) (Rougee et al, 2016). A recent study developed a physiologically based pharmacokinetics (PBPK) model to predict the absorption profiles of vismodegib, an antineoplastic agent with unique nonlinear oral PK properties (Lin et al, 2022).…”

SAAM II: A general mathematical modeling rapid prototyping environment

“… 2 , 28 , 29 , 30 Other groups also use SAAM II for PBPK applications because of its automatic enforcement of balance of mass through its user interface, as well as its ability to create structures like organs, tissues, or (dynamic) cell components for non‐conventional problems that cannot be easily addressed by standard software. PBPK models based on SAAM II were recently used to study the nonlinear absorption and distributions of anticancer drugs 31 , 32 ; another use is in the rapid prototyping of alternative PBPK mechanisms for nanoparticles or macromolecule distribution. 33 , 34 , 35 , 36 Lastly, SAAM II is frequently used in isotope and radio tracing PK/PD and PBPK modeling.…”