Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 2, pp 563–571 | Cite as

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

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

Bexarotene Atorvastatin Pharmacokinetics Non-small cell lung cancer 

Notes

Acknowledgments

This investigation was supported by Ligand Pharmaceuticals, and after this investigation was completed, Eisai Inc acquired Targretin® Capsules from Ligand Pharmaceuticals. This investigation was supported in part by the National Center for Research Resources, National Institutes of Health grant M01 RR-00070 (Stanford University, GCRC). The authors acknowledge the work of many former employees of Ligand Pharmaceuticals, most notably Shawn Flanagan for trial management and Gordon Loewen for PK analysis. The authors acknowledge the work of Lisa A. Hammond-Thelin MD with manuscript preparation and with patient enrollment at the Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center San Antonio, TX, USA.

Conflict of interest

Dr. Arturo Lopez-Anaya was an employee of Eisai Pharmaceuticals at the time of his work on this manuscript. All other authors have no conflict of interest with regard to financial or personal relationships with other people or organizations that could inappropriately influence this work.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

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

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