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Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 3, pp 815–824 | Cite as

A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)

  • Heather A. Wakelee
  • Gary Middleton
  • David Dunlop
  • Rodryg Ramlau
  • Natasha Leighl
  • Desiree Hao
  • Arturo Lopez-Anaya
  • Petr Zatloukal
  • Charlotte D. Jacobs
Clinical Trial Report

Abstract

Purpose

This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin®) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.

Methods

Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m2 on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m2 weekly. Continuous oral bexarotene therapy (400 mg/m2/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2–4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.

Results

Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.

Conclusions

Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

Keywords

Bexarotene Pharmacokinetics Cisplatin Vinorelbine 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. The authors acknowledge the work of former employees of Ligand Pharmaceuticals, most notably Karen Cox and Gordon Loewen in conduct of the trial and PK analysis. This investigation was supported in part by the National Center for Research Resources, National Institutes of Health grant M01 RR-00070 (Stanford University, GCRC).

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
  • Gary Middleton
    • 2
  • David Dunlop
    • 3
  • Rodryg Ramlau
    • 4
  • Natasha Leighl
    • 5
  • Desiree Hao
    • 6
  • Arturo Lopez-Anaya
    • 7
    • 9
  • Petr Zatloukal
    • 8
  • Charlotte D. Jacobs
    • 1
  1. 1.Division of Oncology, Department of MedicineStanford University and Stanford Cancer InstituteStanfordUSA
  2. 2.St. Luke’s Cancer Centre, Royal Surrey County HospitalGuildfordUK
  3. 3.Beatson West of Scotland Cancer CentreGlasgowUK
  4. 4.Poznan University of Medical SciencesPoznanPoland
  5. 5.Princess Margaret HospitalTorontoCanada
  6. 6.Tom Baker Cancer CentreCalgaryCanada
  7. 7.Eisai, Inc.Woodcliff LakesUSA
  8. 8.Third Faculty of MedicineCharles University, Faculty Hospital Bulovka and Postgraduate Medical InstitutePragueCzech Republic
  9. 9.Forest Laboratories, Inc.New HavenUSA

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