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
- 350 Downloads
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.
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).
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.
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.
KeywordsBexarotene Atorvastatin Pharmacokinetics 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. 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.
- 2.Backman JT, Luurila H, Neuvonen M, Neuvonen PJ (2005) Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 78:154–167Google Scholar
- 3.Bexarotene (Targretin) for cutaneous T-cell lymphoma. Med Lett Drugs Ther 42:31–32 (2000)Google Scholar
- 4.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
- 11.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
- 12.Ligand-Pharmaceuticals (2000) Targretin product monographGoogle Scholar
- 15.Park J-E, Kim K-B, Bae SK, Moon B-S, Liu K-H, Shin J-G (2008) Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin. Xenobiotica 38(9):1240–1251Google Scholar
- 16.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
- 18.Rodon J, Jacobs CD, Chu Q, Rowinsky EK, Lopez-Anaya A, Takimoto C, 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
- 23.Wakelee HA, Middleton G, Dunlop D, Ramlau R, Leighl N, Hao D, Lopez-Anaya A, Zatloukal P, Jacobs CD (2011) A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). Cancer Chemother Pharmacol. doi: 10.1007/s00280-011-1771-0