title: 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.
authors.affiliation: Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave, Iowa City, Iowa, 52242, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, 32827, USA.
authors.forename: Jiexin
authors.initials: J
authors.lastname: Deng
authors.affiliation: Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave, Iowa City, Iowa, 52242, USA.
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Murry
authors.affiliation: Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave, Iowa City, Iowa, 52242, USA. guohua-an@uiowa.edu.|Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, 32827, USA. guohua-an@uiowa.edu.
authors.forename: Guohua
authors.initials: G
authors.lastname: An
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D000077156:Gefitinib; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D015233:Models, Statistical; D009369:Neoplasms / Q000378:metabolism; D010599:Pharmacokinetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib
keywords: gefitinib; human scale-up; physiologically based pharmacokinetic model; tyrosine kinase inhibitor