The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer
| Autor: | Arturo Lopez-Anaya, Desiree Hao, Gary Middleton, Rodryg Ramlau, Natasha B. Leighl, Eric K. Rowinsky, J. Rodon, Heather A. Wakelee, D. Dunlop, Petr Zatloukal, Charlotte Jacobs, Quincy Chu, Chris H. Takimoto |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Cancer Research Lung Neoplasms Tetrahydronaphthalenes Metabolic Clearance Rate medicine.medical_treatment Atorvastatin Hypercholesterolemia Pharmacology Toxicology Vinorelbine Drug Administration Schedule chemistry.chemical_compound Pharmacokinetics Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) Drug Interactions Pyrroles Aged Bexarotene Cisplatin Hypertriglyceridemia Chemotherapy Fenofibrate business.industry Middle Aged Carboplatin Treatment Outcome Oncology chemistry Heptanoic Acids Area Under Curve lipids (amino acids peptides and proteins) Female business medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 69(2) |
| ISSN: | 1432-0843 |
| Popis: | Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents.Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene).Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions.A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene. |
| Databáze: | OpenAIRE |
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