Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin*1

Joel, Simon P.; Papamichael, D.; Richards, F. J.; Davis, Theresa; Aslanis, Vassilios; Chatelut, Étienne; Locke, Kathryn; Slevin, M. L.; Seymour, Michel

doi:10.1016/j.clpt.2004.03.008

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…In vismodegib-treated patients, levels of vismodegib (12), oxaliplatin (20,21), irinotecan (22), 5-FU (19,23), and bevacizumab (24) were within the expected ranges for the doses administered ( Supplementary Figs. SA1-SA5).…”

Section: Pharmacokineticsmentioning

confidence: 99%

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A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

155

120

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Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P ¼ 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

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Section: Pharmacokineticsmentioning

confidence: 99%

“…Hence, we focused our Hedgehog ligand predictive biomarker analysis using qRT-PCR assay methodology. A total of 165 (83%) patients provided tumor tissue adequate for determining KRAS mutation status (19).…”

Section: Patient Populationmentioning

confidence: 99%

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

155

120

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“…The plasma protein binding of 5-FU is low, and it is metabolized mainly by hepatic transformation. In fact, oxaliplatin has been reported not to influence pharmacokinetics of 5-FU (Joel et al 2004;Cattel et al 2003). No report addresses the direct effect of 5-FU on the pharmacokinetics of oxaliplatin; however, comparative data indicate that the pharmacokinetics of oxaliplatin are unaffected by 5-FU (Extra et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer

Cho¹,

Lee

et al. 2006

J Cancer Res Clin Oncol

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This study shows that pharmacokinetics of oxaliplatin in Korean patients is comparable with that of other ethic groups, except for the higher C (max) ratios of total/free. The C (max) of 5-FU in plasma showed large variations among patients. Antitumor efficacy in Korean advanced colorectal cancer patients given oxaliplatin and 5-FU should be further evaluated with respect to pharmacokinetic variabilities.

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“…5 Oxaliplatin is mainly eliminated by the kidneys and 5-FU is catabolized by dihydropyrimidine dehydrogenase. Approximately 70% of these metabolites are excreted in urine (21).…”

Section: Discussionmentioning

confidence: 99%

Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors

Siegel-Lakhai

Beijnen

Vervenne

et al. 2007

Clinical Cancer Research

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Purpose: This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/ 5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated. Experimental Design:This study was conducted in two parts. Part1was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study. Results: A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed. Conclusion: Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.Molecular target-specific therapeutics have the potential to improve antitumor activity while minimizing toxicity to normal host cells. ErbB1 (epidermal growth factor receptor) and ErbB2 overexpression can promote tumor growth in a variety of epithelial tumors. In some tumors, such overexpression correlates with a poor clinical outcome, making these receptors attractive therapeutic targets (1 -4). Kinase activation of the ErbB1 and ErbB2 receptors leads to interaction with other signal transduction molecules, initiating an intracellular signaling cascade, which promotes proliferation [mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway] and survival (phosphatidylinositol 3-kinase pathway) of these tumors (5). Therapeutic monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting ErbB1 and/or ErbB2 have been developed. Monoclonal antibodies target the extracellular domain of the tyrosine kinase receptor, and small molecules compete with ATP for the ATP-binding pocket in the cytoplasmic domain of the receptor (6).Lapatinib (GW572016) is an orally active small molecule that reversibly inhibits the phosphorylation of ErbB1 and ErbB2 tyrosine kinases. IC 50 values against ErbB1 and ErbB2 are 10.2 and 9.8 nmol/L, respectively (7). Because ErbB2-containing heterodimers exert potent mitogenic signals...

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Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin*1

Abstract: The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.

Cited by 20 publications

References 21 publications

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer

Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors

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