Norihiro Iwamoto

Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study

Objectives To examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS). Design A prospective observational cohort study. Setting Intensive care unit in a teaching hospital. Participants 85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria. Interventions HRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method. Primary and secondary outcomes The primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia. Results Higher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity. Conclusions Pulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer

AIMS We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer. MATERIALS & METHODS After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC. RESULTS The trough concentration at steady state in patients with the ABCB1 1236TT-2677TT-3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012). CONCLUSION The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial

A multi-institutional phase II trial was conducted to evaluate the efficacy and toxicity of combination chemotherapy consisting of gemcitabine and UFT, which is composed of tegafur and uracil, for non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC received an oral administration of UFT (tegafur 200 mg m−2) b.i.d. from days 1 to 14 and intravenous injection of gemcitabine 900 mg m−2 on days 8 and 15. This treatment was repeated every 4 weeks. A total of 44 patients were enrolled into this trial. The median age of all patients was 74 years, with 23 patients younger than 75 years and 21 patients with 75 years of age or older. A total of 18 patients (41%) achieved a partial response. The median survival time was 13.2 months and the 1-year survival rate was 59%. The most common grade 3–4 toxicity was neutropenia (57%). The frequency of grade 3 nonhaematologic toxicities was less than 5%. In addition, no significant difference in the response, survival or toxicities was observed between the patients younger than and those older than 75 years of age. This combination chemotherapy demonstrated a promising effectiveness and acceptable toxicity in patients with advanced NSCLC, even in patients older than 75 years.

Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.

Abstract 5481: Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, a 150 mg daily dose of which has been shown to be effective for improving overall survival in non-small-cell lung cancer (NSCLC) patients who had failed at least 1 prior chemotherapy regimen. Furthermore, erlotinib demonstrated significant prolongation of progression-free survival versus standard chemotherapy in EGFR mutation positive NSCLC patients. However, skin rash and diarrhea often occurs, and these toxicities lead to discontinuation of therapy or dose reduction in many patients. Several population pharmacokinetics (PK) analyses have reported large interindividual variabilities in erlotinib blood exposure and its toxicities. However, none of those analyses clearly explains the determinants of these large interindividual variabilities. Here, aiming to develop a dose regimen that would maintain the clinical benefits of erlotinib while minimizing its adverse effects, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and interindividual variabilities in the PK and adverse effects. Methods: We performed a multicenter study of 50 patients treated with 150 mg erlotinib as a second-line or later treatment. PK and toxicity were assessed. For PK analyses, blood samples were collected from 28 patients at 5 to 18 time points, and trough blood samples were collected from 20 patients at 1 time point. SNPs in genes encoding metabolizing enzymes or efflux transporters (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, GSTT1, ABCB1, and ABCG2) were analyzed. Population PK analyses were carried out using NONMEM. SNPs were tested as covariates in a population PK model. The effects of these SNPs and erlotinib exposure on toxicity were evaluated. Results and Discussion: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C>T polymorphism was a statically significant covariate for CL/F, showing a 29.4% decrease in CL/F for the TT genotype as compared with the CC and the CT genotypes. The interindividual variability in CL/F decreased by 10.6% after inclusion of the TT genotype as a covariate in the model. This result indicates that a dose reduction to 100 mg for the TT genotype group could equalize the erlotinib exposure between each genotype group. A higher incidence of adverse effects (mainly diarrhea) was observed in the TT genotype group. Conclusions: Of the 20 SNPs that are related to erlotinib PK, only ABCB1 1236C>T influenced the exposure of erlotinib. This SNP was suggested to be related to the risk of adverse events. Individual dosing based on ABCB1 genotype might reduce the adverse effects. Further clinical trials are needed to investigate the toxicity and the clinical outcome of this dose regimen. Citation Format: Chihiro Endo-Tsukude, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada. Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2015-5481

Abstract 5459: Association of CYP1A1 and CYP3A5 polymorphisms with pharmacokinetics of erlotinib in patients with non-small cell lung cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL 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