Abstract
Background: Erlotinib is a selective inhibitor of EGFR tyrosine kinase activity used for the treatment of patients with NSCLC. It has been reported that ABCB1 polymorphisms affect ...pharmacokinetics and adverse events of erlotinib in Japanese patients (Hamada A, 2009 AACR meeting). Erlotinib is metabolized by CYP3A4, CYP3A5, CYP1A1, and CYP1A2. The purpose of this study was to investigate the association of CYP1A1 and CYP1A5 single nucleotide polymorphisms (SNPs) with inter-individual variability of erlotinib pharmacokinetics.
Methods: Patients with NSCLC were treated with single-agent oral erlotinib 150 mg/day. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1 and at steady state (>day 8). DNA was obtained from whole blood, and genotyping was carried out using an Applied Biosystems TaqMan SNP Genotyping Assay on an ABI PRISM® 7900HT system.
Results: Fifty patients (mean age, 67 years) were enrolled in the study. Histological classifications were: adenocarcinoma (n=41), squamous cell carcinoma (n=7), and unknown (n=2). Smoking history was indicated as: never smoker (n=23), former smoker (n=24), and current smoker (n=3). For the CYP3A5 6986A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 6%, 34%, and 60%, respectively. For the CYP1A1 2455A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 64%, 24%, and 12%, respectively. The mean (±SD) maximum concentrations (Cmax), trough concentrations (Ctrough) on day 1, and steady-state trough concentrations (Css) on >day 8 were 1.66±0.73 μg/mL, 0.77±0.5 μg/mL, and 1.5±0.8 μg/mL, respectively. Lower exposure levels of erlotinib were observed in patients carrying the CYP3A5 6986AA allele than in patients carrying one or two G alleles (GA, GG). The Cmax on day 1 in patients carrying the CYP3A5 AA and GA/GG alleles were 0.76±0.27 μg/mL and 1.78±0.69 μg/mL, respectively. (p=0.0198) On the other hand, patients carrying the CYP1A1 2455GG allele had higher Css than in patients carrying the CYP1A1 2455AA or the CYP1A1 2455GA alleles (2.3±1.16 μg/mL vs. 1.4±0.69 μg/mL, p=0.0161)
Conclusion: These results suggested that the CYP3A5 6986A>G and CYP1A1 2455A>G polymorphisms affect the pharmacokinetics of erlotinib in Japanese patients. Further studies involving a larger sample size will be required to evaluate whether measurement of the CYP3A5 and the CYP1A1 polymorphisms may help to optimize erlotinib treatment in individual patients.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5459. doi:10.1158/1538-7445.AM2011-5459
Abstract
Erlotinib is an oral available, selective inhibitor of EGFR tyrosine kinase activity for the treatment of patients with NSCLC. Side effects, commonly seen as skin rash and diarrhea, occurred ...in 75% of patients. About 20% of patients needed erlotinib dose reduction from the standard dose of 150mg/day due to these toxicities. Since the severity of skin rash is strongly associated with improved clinical outcome, skin rash may be a surrogate marker of favorable clinical outcome. Erlotinib is a substrate for ABC transporters such as ABCB1 and ABCG2. However, it is unknown whether these polymorphisms affect the pharmacokinetics of erlotinib and influence the inter-individual variability in erlotinib toxicity. The purpose of this study is to evaluate the effects of ABC transporter polymorphism on erlotinib pharmacokinetics and the development of side effects, skin rash and diarrhea in Japanese patients with NSCLC.
Methods: Thirty-one Patients were orally administered 150 mg erlotinib as a single treatment. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1(D1), 8(D8), and stable phase. DNA from plasma was screened for SNPs in the ABCB1 and ABCG2 genes using TaqMan assay or direct nucleotide sequencing. Results: The mean Cmax of D1 and D8 were 1.7 and 3.1 µg/ml, respectively. Trough concentration at D1, D8 and steady state were 0.7, 1.2 and 1.4 µg/ml, respectively. Skin rash occurred in 95% of patients. One patient (Cmax, 3.0 µg/ml at D1) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The Cmax and AUC on D1 was correlated with the severity of skin rash, however, Cmin were not correlated. Patients with homozygous variant for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type and heterozygous were associated with higher AUC and Cmin at D1 (31 vs 21, p=0.07; 1.1 vs 0.6 µg/ml, p=0.007). AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. ABCB1 polymorphism was associated with decreased ABCB1 function, resulting in the increased concentration of erlotinib. All five patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT developed higher grade 2 toxicity by day 7. Patients homozygous variant for ABCB1 developed toxicity significantly faster than those with at least one T allele (p=0.002). On the other hand, all three patients carrying without T allele had not experience toxicity.
Conclusions: The present study suggests that ABCB1 polymorphism affects the pharmacokinetics of erlotinib and also influence the development of erlotinib toxicity. We proposed that prior to the Erlotinib treatment, the measuring of ABCB1 polymorphism may help to identify patients with NSCLC who can develop a severe toxicity.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3588.
We performed thoracoscopy in patients with pleural effusion of unknown origin. Thoracoscopy was performed by flexible bronchoscopes under local anesthesia in 120 patients with pleural effusion that ...was characterized by being exudative in nature, lymphocyte-dominant, with low levels of adenosine deaminase, and no malignant cells. Of those 36 cases were outpatients. A catheter was inserted into the pleural space under local anesthesia, pleural effusion was drained by an aspirator, and 300 to 500 ml of oxygen was injected to create an artificial pneumothorax. A flexible bronchoscope was inserted into the pleural space via another incision. Observation and biopsy was performed for 10 to 20 minutes. Thoracoscopy by the flexible bronchoscope which is most familiar to bronchoscopists is a very simple and easy procedure without any major side effects, and has a high diagnostic yield. (JJSB. 2004;26:343-345)
Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. ...We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
An open-label, single-arm prospective study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine and tegafur-uracil (UFT) in patients with advanced nonsmall-cell lung ...cancer (NSCLC) after the failure of previous platinum-containing regimens.
Patients with advanced NSCLC received 200 mg/m2 of UFT twice daily from day 1 through 14 plus 900 mg/m2 of gemcitabine per day via intravenous injection on days 8 and 15. This regimen was repeated every 3 or 4 weeks.
A total of 40 patients were enrolled. Eleven patients (28%; 95% confidence interval CI, 15–44%) achieved a partial response. The median progression-free survival, median overall survival, and 1-year survival rate were 4.0 months (95% CI, 3.3–6.7 months), 12.6 months (95% CI, 7.0–22.3 months), and 51% (95% CI, 33–66%), respectively. The most common grade 3 or 4 toxicity was neutropenia (38%; 95% CI, 23–54%) and the rate of grade 3 or 4 nonhematologic toxicity remained at less than 5%. A multivariate Cox model showed that adenocarcinoma, nonsmoking history, and good performance status predicted better survival.
Combination chemotherapy with UFT and gemcitabine showed a promising effectiveness and acceptable toxicity for patients with platinum-resistant NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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