Journal article
A Whole-Body Physiologically Based Pharmacokinetic Model of Gefitinib in Mice and Scale-Up to Humans
The AAPS journal, Vol.18(1), pp.228-238
01/2016
DOI: 10.1208/s12248-015-9836-3
PMCID: PMC4706283
PMID: 26559435
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.
Details
- Title: Subtitle
- A Whole-Body Physiologically Based Pharmacokinetic Model of Gefitinib in Mice and Scale-Up to Humans
- Creators
- Youwei Bi - grid.214572.7 0000000419368294 Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy University of Iowa 115 S Grand Ave Iowa City Iowa 52242 USAJiexin Deng - grid.170430.1 0000000121592859 Department of Pharmaceutics, College of Pharmacy University of Florida Orlando Florida 32827 USADaryl Murry - grid.214572.7 0000000419368294 Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy University of Iowa 115 S Grand Ave Iowa City Iowa 52242 USAGuohua An - grid.170430.1 0000000121592859 Department of Pharmaceutics, College of Pharmacy University of Florida Orlando Florida 32827 USA
- Resource Type
- Journal article
- Publication Details
- The AAPS journal, Vol.18(1), pp.228-238
- Publisher
- Springer US; New York
- DOI
- 10.1208/s12248-015-9836-3
- PMID
- 26559435
- PMCID
- PMC4706283
- ISSN
- 1550-7416
- eISSN
- 1550-7416
- Language
- English
- Date published
- 01/2016
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Holden Comprehensive Cancer Center
- Record Identifier
- 9984065311002771
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