Gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and bexarotene (a rexinoid) affect similar oncogenic pathways and are both metabolized through cytochrome P450 CYP3A4. We studied the combination of bexarotene and gefitinib in the third-line treatment of advanced non-small-cell lung cancer to examine pharmacokinetic interactions and establish the maximum tolerated dose. This was a single-institution, nonrandomized, open-label, phase I clinical trial with a standard 3+3 dose escalation. Three patients were enrolled at each dose level on the basis of pharmacokinetic analysis with dose level 1 including gefitinib (Iressa) 250 mg oral daily and bexarotene (Targretin) 400 mg/m2 oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m2 oral daily. Patients received gefitinib alone for 2 weeks to allow for steady state and thereafter, bexarotene was added. In dose level 1, two of three patients had undetectable gefitinib levels at day 15 for unknown reasons. However, the peak levels on day 29 for all three patients receiving 250 mg of gefitinib with bexarotene are lower than published peak levels. Among the three patients in dose level +1, ∼40% lower gefitinib plasma concentrations were noted on day 29 compared with day 15 along with a mean 44% reduction in area under the plasma concentration–time curve from 0 to 24 h (AUC0–24). Bexarotene appears to lower the Cmax and AUC0–24 of gefitinib through cytochrome P450 CYP3A4. Our results have pharmacokinetic implications for ongoing trials that combine bexarotene with other small molecules in the era of personalized cancer therapy.
aDepartment of Medicine, Division of Oncology
bDepartment of Medicine, Division of Pulmonary, Stanford Cancer Institute, Stanford University, Stanford, California
cDepartment of Pharmacokinetics and Pharmacodynamics, PKPD PG Rx Consultant LLC, East Lyme, Connecticut, USA
Correspondence to Heather A. Wakelee, Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA Tel: +1 650 736 7221; fax: +1 650 724 3697; e-mail: firstname.lastname@example.org
Received January 27, 2013
Accepted March 7, 2013