A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)
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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.
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.
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.
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).
KeywordsBexarotene Pharmacokinetics Cisplatin Vinorelbine Non-small-cell lung cancer
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.
- 2.Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A (2008) Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol 26:1879–1885PubMedCrossRefGoogle Scholar
- 5.Brabender J, Metzger R, Salonga D, Danenberg KD, Danenberg PV, Holscher AH, Schneider PM (2005) Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: implications for tumor development and prognosis. Carcinogenesis 26:525–530PubMedCrossRefGoogle Scholar
- 8.clinicaltrials.gov (2008) NCT00411632Google Scholar
- 11.Hermann TW, Yen WC, Tooker P, Fan B, Roegner K, Negro-Vilar A, Lamph WW, Bissonnette RP (2005) The retinoid X receptor agonist bexarotene (Targretin) synergistically enhances the growth inhibitory activity of cytotoxic drugs in non-small cell lung cancer cells. Lung Cancer 50:9–18PubMedCrossRefGoogle Scholar
- 16.Khuri FR, Rigas JR, Figlin RA, Gralla RJ, Shin DM, Munden R, Fox N, Huyghe MR, Kean Y, Reich SD, Hong WK (2001) Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 19:2626–2637PubMedGoogle Scholar
- 18.Mahmood I (2005) Interspecies pharmacokinetic scaling: principles and application of allometric scaling. Pine House Publishers, MarylandGoogle Scholar
- 23.Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Pereira JR, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE (2008) Randomized phase III trial comparing bexarotene (L1069–49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol 26:1886–1892PubMedCrossRefGoogle Scholar
- 25.Rodon J, Jacobs CD, Chu Q, Rowinsky EK, Lopez-Anaya A, Takimoto CH, Wakelee HA (2011) A phase I pharmacokinetic study of bexarotene with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Cancer Chemother Pharmacol. doi: 10.1007/s00280-011-1770-1
- 29.Wakelee H, Middleton G, Dunlop D, Kelly C, Ramlau R, Leighl NB, Hao D, Zatloukal P, Loewen G, Cox K, Jacobs C (2005) Effect of bexarotene on vinorelbine and cisplatin pharmacokinetics (PK) during a Phase I study in patients with advanced non-small cell lung cancer (NSCLC). Lung Cancer 49(Suppl 2):S274 (Abstr #P-592)CrossRefGoogle Scholar
- 30.Wakelee H, Takimoto CH, Lopez-AnayaA, Chu Q, Middleton G, Dunlop D, Ramlau R, Leighl N, Rowinsky EK, Hao D, Zatloukal P, Jacobs CD, Rodon J (2011) 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. Cancer Chemother Pharmacol. doi: 10.1007/s00280-011-1772-z