title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Oncology, Department of Medicine, Stanford University and Stanford Cancer Institute, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA. hwakelee@Stanford.edu
authors: Heather A
authors: HA
authors: Wakelee
authors: Chris H
authors: CH
authors: Takimoto
authors: Arturo
authors: A
authors: Lopez-Anaya
authors: Quincy
authors: Q
authors: Chu
authors: Gary
authors: G
authors: Middleton
authors: David
authors: D
authors: Dunlop
authors: Rodryg
authors: R
authors: Ramlau
authors: Natasha
authors: N
authors: Leighl
authors: Eric K
authors: EK
authors: Rowinsky
authors: Desiree
authors: D
authors: Hao
authors: Petr
authors: P
authors: Zatloukal
authors: Charlotte D
authors: CD
authors: Jacobs
authors: Jordi
authors: J
authors: Rodon
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D000069059:Atorvastatin; D000077610:Bexarotene; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D015228:Hypertriglyceridemia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D013764:Tetrahydronaphthalenes; D000069059:Atorvastatin; D000077610:Bexarotene