© The Author 2006. Published by Oxford University Press.
ARTICLE |
CYP3A Phenotyping Approach to Predict Systemic Exposure to EGFR Tyrosine Kinase Inhibitors
Affiliations of authors: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD (JL, JB, AS, MZ, MH, SDB); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (MOK)
Correspondence to: Sharyn D. Baker, PharmD, PhD, Pharmaceutical Sciences Department, St Jude Children's Research Hospital, 332 North Lauderdale St., DTRC Rm. D1034, Mail Stop 314, Memphis, TN 38105 (e-mail: sharyn.baker{at}stjude.org).
Background: Gefitinib is an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) with activity in non–small-cell lung cancer. The response to gefitinib is variable, possibly because of interindividual variation in the activity of cytochrome P450 3A (CYP3A), the principal enzyme that metabolizes gefitinib. We prospectively assessed the influence of CYP3A activity on gefitinib disposition and toxicity. Methods: Twenty-seven patients with advanced cancer were treated with daily oral gefitinib at 250 mg (n = 13) or 500 mg (n = 14) for 28 days. Concentration–time profiles of midazolam and geftinib were constructed based on measurement of their concentration in serial blood samples using high-performance liquid chromatography and mass spectroscopy. CYP3A activity was determined at baseline by assessment of midazolam apparent oral clearance. Pharmacokinetic studies were performed for a period of 28 days, and population modeling was performed using NONMEM software. A structural pharmacokinetic model was developed to describe the concentration–time profiles of unbound and total gefitinib plasma concentrations, and patient-specific covariates were added to the model to account for unexplained interindividual variability in pharmacokinetic parameters. Statistical tests were two-sided. Results: Gefitinib pharmacokinetics exhibited wide interindividual variability (interindividual variability on total and unbound gefitinib apparent oral clearance was 79% and 74%, respectively). Midazolam clearance (mean = 40 L/h, range = 10–111) was highly correlated with that of total and unbound gefitinib (R2 = .60 and R2 = .68, respectively) and with steady-state plasma trough concentrations of gefitinib (R2 = .58 and R2 = .60, respectively), and it accounted for approximately 40% of interindividual variability in gefitinib clearance in the pharmacokinetic model. Both total and unbound gefitinib steady-state plasma trough concentrations were associated with the development of diarrhea (P<.05), but not skin rash. At a dose of 250 mg gefitinib, 11 of 13 patients achieved steady-state plasma trough concentrations above the IC50 for inhibition of mutant EGFR in vitro (0.015 µM), but only one achieved a steady-state plasma trough concentration above the IC50 for inhibition of wild-type EGFR (0.1 µM). Conclusions: As an in vivo phenotypic probe of CYP3A, midazolam oral clearance may have utility for prediction of gefitinib exposure and dose selection. A pharmacokinetic model incorporating this indicator of CYP3A activity has potential for optimization of treatment with gefitinib and other TK inhibitors that are metabolized in a similar manner.
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