A Whole-Body Physiologically Based Pharmacokinetic Model of Gefitinib in Mice and Scale-Up to Humans

Abstract

Gefitinib (Iressa) is a selective and potent EGFR tyrosine kinase inhibitor. It received an accelerated FDA approval in 2003 for the treatment of patients with nonsmall cell lung cancer (NSCLC) and represents the first-line therapy for NSCLC with EGFR mutations. In the work presented herein, the disposition of gefitinib was investigated extensively in mouse in both plasma and 11 organs (liver, heart, lung, spleen, gut, brain, skin, fat, eye, kidney, and muscle) after a single IV dose of 20 mg/kg. Gefitinib demonstrated extensive distribution in most tissues, except for the brain, and tissue to plasma partition coefficients (K pt) ranged from 0.71 (brain) to 40.5 (liver). A comprehensive whole-body physiologically based pharmacokinetic (PBPK) model of gefitinib in mice was developed, which adequately captured gefitinib concentration-time profiles in plasma and various tissues. Predicted plasma and tissue AUC values agreed well with the values calculated using the noncompartmental analysis (<25% difference). The PBPK model was further extrapolated to humans after taking into account the interspecies differences in physiological parameters. The simulated concentrations in human plasma were in line with the observed concentrations in healthy volunteers and patients with solid malignant tumors after both IV infusion and oral administration. Considering the extensive tissue distribution of gefitinib, plasma concentration may not be an ideal surrogate marker for gefitinib exposure at the target site or organ of toxicity (such as the skin). Since our whole-body PBPK model can predict gefitinib concentrations not only in plasma but also in various organs, our model may have clinical applications in efficacy and safety assessment of gefitinib.

Keywords: gefitinib; human scale-up; physiologically based pharmacokinetic model; tyrosine kinase inhibitor.

Fig. 1

Schematic representation of a physiologically based pharmacokinetic model for gefitinib in the mouse

Fig. 2

Model structure for perfusion rate-limited kinetics and permeability rate-limited kinetics

Fig. 3

Gefitinib concentrations in plasma and in 11 examined tissues (brain, eye, fat, gut, spleen, heart, kidney, liver, lung, muscle, skin, spleen) following intravenous bolus administration of 20 mg/kg gefitinib in mice. Three mice were used at each time point

Fig. 4

Observed (dots) and predicted (lines) gefitinib concentrations in plasma and various organs/tissues in mice. Each dot and vertical bar represents the mean and 95% CI of the observations, respectively. Solid lines are the fit predictions based on the proposed PBPK model

Fig. 5

Observed and PBPK model-simulated plasma concentrations of gefitinib following different dosing regimens in both healthy subjects and patients with solid tumors. Measured gefitinib data (black dots) was digitalized from following published articles: a–c Swaisland et al. (17); d Nakagawa et al. (38). Solid lines and dotted lines represent the mean and 90% CI of the simulations from the proposed PBPK model, respectively