Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 2, pp 563–571

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

  • Heather A. Wakelee
  • Chris H. Takimoto
  • Arturo Lopez-Anaya
  • Quincy Chu
  • Gary Middleton
  • David Dunlop
  • Rodryg Ramlau
  • Natasha Leighl
  • Eric K. Rowinsky
  • Desiree Hao
  • Petr Zatloukal
  • Charlotte D. Jacobs
  • Jordi Rodon
Clinical Trial Report

DOI: 10.1007/s00280-011-1772-z

Cite this article as:
Wakelee, H.A., Takimoto, C.H., Lopez-Anaya, A. et al. Cancer Chemother Pharmacol (2012) 69: 563. doi:10.1007/s00280-011-1772-z

Abstract

Purpose

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/m2/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.

Keywords

BexaroteneAtorvastatinPharmacokineticsNon-small cell lung cancer

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Heather A. Wakelee
    • 1
  • Chris H. Takimoto
    • 2
    • 11
  • Arturo Lopez-Anaya
    • 3
    • 12
  • Quincy Chu
    • 2
    • 13
  • Gary Middleton
    • 5
  • David Dunlop
    • 6
  • Rodryg Ramlau
    • 7
  • Natasha Leighl
    • 8
  • Eric K. Rowinsky
    • 2
    • 14
  • Desiree Hao
    • 9
  • Petr Zatloukal
    • 10
  • Charlotte D. Jacobs
    • 1
  • Jordi Rodon
    • 2
    • 15
  1. 1.Division of Oncology, Department of MedicineStanford University and Stanford Cancer InstituteStanfordUSA
  2. 2.Institute for Drug DevelopmentCancer Therapy and Research Center at The University of Texas Health Science CenterSan AntonioUSA
  3. 3.Eisai, Inc.Woodcliff LakesUSA
  4. 4.Department of OncologyUniversity of Alberta, Cross Cancer InstituteEdmontonCanada
  5. 5.St. Luke’s Cancer CentreRoyal Surrey County HospitalGuildfordUK
  6. 6.Beatson West of Scotland Cancer CentreGlasgowUK
  7. 7.Poznan University of Medical SciencesPoznanPoland
  8. 8.Princess Margaret HospitalTorontoCanada
  9. 9.Tom Baker Cancer CentreCalgaryCanada
  10. 10.Third Faculty of Medicine, Faculty Hospital Bulovka and Postgraduate Medical InstituteCharles UniversityPragueCzech Republic
  11. 11.Ortho Biotech Oncology R&D/Johnson & JohnsonRadnorUSA
  12. 12.Forest Laboratories, Inc.New HavenUSA
  13. 13.Cross Cancer InstituteUniversity of AlbertaEdmontonCanada
  14. 14.Oncodrugs ConsultingWarrenUSA
  15. 15.Vall d’Hebron University Hospital and Vall d’Hebron Institute of OncologyBarcelonaSpain