Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice

Abstract

Purpose: This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice.

Methods: A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice.

Results: Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, through hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knockout mouse.

Conclusions: Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure-dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.

Keywords: Efflux transporters; Influx transporters; Physiologically based pharmacokinetics; Sensitivity analysis; Sorafenib.

Figure 1

Whole body PBPK model structure (left). Structure of Sorafenib and Sorafenib metabolite model including transporters (ovals) and metabolism processes in liver and gastrointestinal (GI) lumen (right).

Figure 2

Plasma (circles) and liver (squares) concentration time profiles following sorafenib administration to WT (black symbols) and Oatp1a/1b KO (red symbols) mice. The shaded region shows the variability in the disposition when SG Oatp1a/1b activity is decreased from the baseline value to 0.

Figure 3

SG (a) and sorafenib (b) disposition given a 10 mg/kg dose of SG to WT mice either treated with saline (black circles) or neomycin (red circles). The shaded region shows the variability in the disposition when β-glucuronidase activity is decreased 2 fold from baseline.

Figure 4

Uncertainty analysis: Symbols present the WT FVB mouse plasma (circles) and liver (squares) concentration time data. The blue shaded region represents 25^th–75^th percentile in the variability of the concentrations and the gray shaded region represents the range.

Figure 5

Sorafenib and SG efflux via Abcc3. Black circles and curve: WT; Red circles curve: Abcc3 KO. The shaded region shows the variability in the disposition when sorafenib and SG Abcc3 activity are decreased from baseline value to 0.

Figure 6

Sorafenib and SG efflux via Abcc2. Black circles and curve: WT; Red circles and curve: Abcc2 KO. The shaded region shows the variability in the disposition when SG Abcc2 activity is decreased from baseline value to 0 and another undefined sinusoidal membrane efflux transporter’s activity is increased 2 fold.