Pharmacokinetics of gefitinib in elderly patients with EGFR-mutated advanced non-small cell lung cancer: a prospective study.

BACKGROUND: Gefitinib is recommended as a first-line treatment option for elderly patients with non-small cell lung cancer (NSCLC). Because no pharmacokinetics of gefitinib have been examined, we prospectively assessed the pharmacokinetics of gefitinib in patients with epidermal growth factor receptor gene-mutated advanced NSCLC who were 75 years or older. METHODS: Gefitinib was orally administered once daily at a dose of 250 mg. The concentrations of gefitinib and its major metabolite O-desmethyl gefitinib in plasma were measured by high-performance liquid chromatography. The area under the plasma concentration-time curve from time 0 to 48 h (AUC0-48) was calculated. Polymorphisms in CYP3A5, CYP2D6, ABCG2, ABCB1, and OATP1B1 were analyzed by direct sequencing. RESULTS: Eighteen patients with a median age of 80.5 years (range, 75-89) with adequate liver and kidney functions were examined. AUC0-48 values of gefitinib and O-desmethyl gefitinib in this population were 9.49 ± 3.5 and 10.6 ± 14 µM h, respectively. Compared to the gefitinib pharmacokinetics observed in a previous phase I study in Japan, systemic exposure to gefitinib in elderly patients was slightly higher than that in younger patients. Three patients experienced grade 3 diarrhea, increases in alanine aminotransferase, and aspartate aminotransferase levels 30 days after starting gefitinib treatment. The CYP2D6 genotype was associated with CYP2D6-mediated metabolism of gefitinib to O-desmethyl gefitinib. CONCLUSIONS: We demonstrated for the first time the systemic exposure to gefitinib in elderly patients with NSCLC. TRIAL REGISTRATION: The study was registered with the University Hospital Medical Information Network-Clinical Trials Registry Japan (UMIN000026409) on November 8, 2013.

A Case of Hepatocellular Carcinoma Successfully Resumed Atezolizumab and Bevacizumab After Associated Grade 3 Diarrhea and Grade 2 Colitis: Case Report and Literature Review.

Systemic chemotherapy has shown a significant survival benefit in patients with hepatocellular carcinoma (HCC). However, it is associated with various immune-related adverse events (irAEs). We report a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone. An 89-year-old man was incidentally detected with a 140-mm hypervascular intrahepatic nodule on contrast-enhanced computed tomography (CECT). Washout of the contrast medium was also detected, and protein induced by vitamin K deficiency or antagonists-II (PIVKA-II) was elevated. Since the Albumin-Bilirubin (ALBI) grade was 2a without any distant metastasis, transarterial chemoembolization (TACE) was performed to treat the HCC, but several intrahepatic nodules were seen in both lobes. Therefore, the patient was treated with lenvatinib for 1 year and 4 months. A complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was achieved in 2 months; however, multiple hypervascular nodules were detected again. Since the ALBI grade was 1, a second round of chemotherapy with atezolizumab and bevacizumab was initiated. Although a complete response was achieved, the therapy was discontinued due to grade 3 diarrhea and grade 2 colitis after the sixth course. Based on the stool analysis and culture, CECT, and colonoscopy, the diagnosis was atezolizumab-associated colitis. Diarrhea was controlled following the oral administration of 0.5 mg/kg/day of prednisolone, and atezolizumab-bevacizumab therapy was successfully reinitiated without recurrence of colitis. The management of irAEs is important for a significant survival benefit. Systemic chemotherapy with atezolizumab and bevacizumab can be resumed despite a grade 3 irAE due to atezolizumab.

Developing a Japanese version of the 'scale of attitudes toward pharmacist-physician collaboration'.

There are many reports that pharmacotherapy has been optimized to ensure collaboration between physicians and pharmacists. Various scales assess the relationship between physicians and pharmacists as well as medical students and pharmacy students. The Scale of Attitudes Toward Physician-Pharmacist Collaboration (SATP2C) can be applied not only to the physician-pharmacist relationship but also to the medical-pharmacy student relationship. As there is no Japanese version of the SATP2C, we developed one and examined its psychometric properties. SATP2C scores were measured before and after interprofessional education (IPE) to verify responsiveness. The scale showed confirmed reliability: Cronbach's alphas were 0.79 for Responsibility and Accountability, 0.68 for Shared Authority, and 0.67 for Interdisciplinary Education. Pre and post-IPE, each mean subscale score increased: Responsibility and Accountability, 0.7 ± 0.4; Shared Authority, 0.2 ± 0.3; and Interdisciplinary Education, 0.3 ± 0.2. Although the total score increased (1.2 ± 0.7), this was non-significant. The Japanese version of the SATP2C can be considered, at least initially, to have reached an acceptable level of reliability and validity. The new measure is currently the only scale in Japan that can evaluate attitudes toward physician-pharmacist collaboration regarding IPE. Further studies are needed to confirm responsiveness pre- and post-IPE.

Prophylactic Quinolone Prescription Patterns Related to Febrile Neutropenia in Cancer Chemotherapy Outpatients.

OBJECTIVE: The aim of this study is to assess prophylactic prescriptions for febrile neutropenia(FN)caused by chemotherapy. INVESTIGATION: We retrospectively surveyed prophylactic antibiotic prescriptions administered to 930 cancer treatment naive outpatients at Showa University Hospital. Factors associated with prophylactic antibiotic prescriptions were assessed based on patient characteristics, intensity of chemotherapy regimens, laboratory data and diagnoses using logistic regression analysis. RESULTS: The number of patients given prophylactic antibiotic prescriptions was significantly higher in high-risk regimens(n= 349)compared to low-risk regimens(n=288), with an odds ratio of 8.93(6.07-13.14). In logistic regression analysis, significant factors affecting the prophylactic prescription of antibiotics were high-risk regimens(OR: 2.05, p=0.009), age(+ 1 year, OR: 0.98, p=0.002), female sex(OR: 7.10, p<0.001), WBC count(+1.0×10 / 3mL, OR: 1.19, p=0.013)and operation history before and after chemotherapy(OR: 23.19, p<0.001). CONCLUSIONS: Physicians(including pharmacists)should therefore pay attention to the prophylactic prescriptions especially in high-risk female cancer patients with operation history. This prescription pattern provides basic information needed for the proper use of antibiotics in cancer patients.

Influence of nonsteroidal anti-inflammatory drugs on the antiplatelet effects of aspirin in rats.

Low-dose aspirin acts by irreversibly acetylating internal cyclooxygenase-1 (COX-1) on platelets, thereby suppressing platelet aggregation. Because nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit COX-1, the antiplatelet effects of aspirin may be suppressed when it is co-administered with NSAIDs. In this study, the influences of ibuprofen, loxoprofen sodium and etodolac on the antiplatelet effects of aspirin were investigated in male Sprague-Dawley (SD) rats. Aspirin and/or NSAIDs were administered orally at single or multiple daily doses. Platelet aggregation (ADP and collagen were added as stimuli) and serum thromboxane B(2) (TXB(2)) concentrations were measured. The maximum inhibitions of aggregation in the aspirin before ibuprofen group were 41.0±7.8% for ADP and 38.7±5.4% for collagen at 6 h after administration; similar values were seen in the aspirin group; however, percent inhibitions in the aspirin before ibuprofen multiple administration group were lower than those in the aspirin group. Thus, the inhibitory effects of daily low-dose aspirin on platelets are competitively inhibited by the prolonged use of multiple daily doses of ibuprofen. In contrast, serum TXB(2) concentrations in all groups were lower than those in the control group (drug-free). This suggests that the relationship between the inhibition of platelet COX-1 and the suppression of platelet aggregation is nonlinear. When aspirin was administered with loxoprofen sodium, similar effects were observed; however, with etodolac, the antiplatelet effects in all groups were equal to those in the aspirin group. Accordingly, if co-administration with NSAIDs is necessary with low-dose aspirin, a selective COX-2 inhibitor, such as etodolac, should be used.