Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Tan, Antoinette R.; Yang, Xiaowei; Hewitt, Stephen M.; Berman, Arlene; Lepper, Erin R.; Sparreboom, Alex; Parr, Allyson; Figg, William D.; Chow, Catherine; Steinberg, Seth M.; Bacharach, Stephen L.; Whatley, Millie; Carrasquillo, Jorge A.; Brahim, Jaime S.; Ettenberg, Seth A.; Lipkowitz, Stan; Swain, Sandra M.

doi:10.1200/jco.2004.08.189

Cited by 162 publications

(87 citation statements)

References 24 publications

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“…Thus the comparison of the PD parameters estimated from different models could be a reasonable approach to predict a clinical response. Tan et al suggested that for cancer patients who were treated with a effective daily dose of 150 mg erlotinib orally, the minimum steady-state concentration (C ss, min ) was 1.473 µg/mL (SD=0.877 µg/mL), the maximum steady-state concentration (C ss, max ) was 2.528 µg/mL (SD=1.187 µg/mL) and the average steady-state concentration (C ss, ave ) was 1.818 µg/mL (SD=0.973 µg/mL) [32] . For this research, the IC 50 for pEGFR degradation was 1.80 µg/mL, which was within the steady-state minimum and maximum concentration window.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

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Aim: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC 50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K bio value of 0.507 cm 3 /week, which described the impact of pEGFR degradation on tumor growth. Conclusion: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

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Section: Discussionmentioning

confidence: 98%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

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“…Importantly, the clinical benefit observed with anti-EGFR tyrosine kinase inhibitors (TKIs) across different disease entities has been variable. For example, EGFR TKIs are largely inactive in colorectal cancer and breast cancer (Tan et al, 2004;Baselga and Arteaga, 2005). Nevertheless, two of these drugs, gefitinib and erlotinib, have demonstrated clinical activity in non small cell lung cancer and responses have been observed in patients with advanced pancreatic cancer and in head-and-neck cancer (Baselga, 2006).…”

Section: Discussionmentioning

confidence: 99%

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

et al. 2008

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Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, Po0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P ¼ 0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P ¼ 0.028; HER2, median survival 18 vs 29 months, P ¼ 0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P ¼ 0.0197; HER2, P ¼ 0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

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“…It is approved for the treatment of advanced nonsmall cell lung cancer as a single agent and advanced pancreatic cancer in combination with gemcitabine. Erlotinib has an average oral bioavailability in humans of 59% (Frohna et al, 2006), but exhibits substantial (up to eight-fold) interindividual pharmacokinetic variability (Hidalgo et al, 2001;Tan et al, 2004), which may result in variable treatment outcomes. Erlotinib is extensively metabolised into multiple products , including an active O-desmethyl metabolite, OSI-420.…”

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confidence: 99%

Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

et al. 2008

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Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Cited by 162 publications

References 24 publications

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

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