Phase I and pharmacokinetic study of bexarotene in combination with gefitinib in the third-line treatment of non-small-cell lung cancer
| Autor: | Sukhmani K. Padda, Laveena Chhatwani, Charlotte Jacobs, Lisa Zhou, Heather A. Wakelee, Arturo Lopez-Anaya |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Cancer Research Lung Neoplasms Tetrahydronaphthalenes Phases of clinical research Pharmacology Cohort Studies Gefitinib Pharmacokinetics Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols medicine Carcinoma Humans Pharmacology (medical) Lung cancer Aged Bexarotene CYP3A4 business.industry Middle Aged medicine.disease respiratory tract diseases Clinical trial Treatment Outcome Oncology Quinazolines Female business medicine.drug |
| Zdroj: | Anti-Cancer Drugs. 24:731-735 |
| ISSN: | 0959-4973 |
| Popis: | 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/m oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m 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 C max 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. |
| Databáze: | OpenAIRE |
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