Papers - KAWAZOE Hitoshi

Efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli

Namiki T, Yokoyama Y, Kimura M, Fukuda S, Seyama S, Iketani O, Jibiki A, Kawazoe H, Ohtani H, Hasegawa N, Mastumoto K, Oda R, Hashi H, Suzuki S, Nakamura T

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan)  in press. 2025.02

Research paper (scientific journal), Joint Work, Accepted

Proton Pump Inhibitors and Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Breast Cancer

Takahashi K, Uozumi R, Mukohara T, Hayashida T, Iwabe M, Iihara H, Kusuhara-Mamishin K, Kitagawa Y, Tsuchiya M, Kitahora M, Nagayama A, Kosaka S, Asano-Niwa Y, Seki T, Ohnuki K, Suzuki A, Ono F, Futamura M, Kawazoe H*, Nakamura T

Oncologist (Oxford University Press)  29 ( 6 ) e741 - e749 2024.06

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  10837159

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Background: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment.
Patients and Methods: This multicenter, retrospective, observational study, conducted across four medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan–Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio.
Results: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival periods were 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% confidence interval [CI], 0.70–2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61–2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Moreover, adverse event incidence and severity were similar in both groups.
Conclusion: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

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Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial

Iihara H, Iwai M, Morita R, Fujita Y, Ohgino K, Ishihara T, Hirose C, Suzuki Y, Masubuchi K, Kawazoe H, Kawae D, Aihara K, Endo S, Fukunaga K, Yamazaki M, Tamura T, Kitamura Y, Fukui S, Endo J, Suzuki A

Lung Cancer (ELSEVIER IRELAND LTD)  192   107801 2024.04

Research paper (scientific journal), Joint Work, Accepted

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Using an online journal club to improve Asian speakers’ comfort in using English to discuss and understand research papers written in English

Tsuchiya M, Saeteaw M, Subongkot S, Tharnpanich T, Konmun J, Nasu I, Shimanuki Y, Tsuchitani T, Ezura M, Hashiguchi K, Bryan JC, Kawazoe H*

Journal of Oncology Pharmacy Practice (SAGE PUBLICATIONS LTD)  in press. 2024.03

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

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Introduction: This study aimed to evaluate the participants’ comfort in understanding research papers written in English and discussing such research in English via an Asian online journal club.
Methods: A self-administered online survey was delivered to seven journal club meeting attendees from July 2020 to July 2021. A customer satisfaction analysis was performed to assess the association between the participants’ perspectives on program logistics and satisfaction.
Results: The recovery rate was 37.0% (44/119). After participating in the journal club, the median scores of critical appraisal skills, knowledge and/or pharmaceutical care skills in clinical practice, and discussion skills in English (assessed using a seven-point Likert scale) improved significantly (compared to pre-participation median scores) from 4 (interquartile range [IQR]: 3–5) to 5 (IQR: 4–6), 5 (IQR: 4–5) to 5 (IQR: 5–6), and 4 (IQR: 2–5) to 5 (IQR: 3–5), respectively (P < 0.0001). The respondents also expressed great appreciation for the benefits and overall qualities of the journal club. Additionally, regarding patient care behavior after participation in the journal club, 34 (77.3%), 17 (38.6%), 16 (36.4%), and 14 (31.8%) respondents reported improvement in “drug information services,” “patient assessments,” “patient counseling,” and “multidisciplinary rounds,” respectively. Customer satisfaction analysis revealed that sharing information, mutual discussion, a shift system of presenters and co-chairs, and session duration should be improved as a matter of highest priority.
Conclusion: The findings suggest that our program could be helpful for Asian pharmacists, pharmacy students, and faculty members of the department of pharmacy.

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Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum β-lactamase producing Enterobacterales (ESBL-E)

Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, Matsumoto K, Suzuki S, Nakamura T

Pharmacotherapy (WILEY)  44 ( 2 ) 149 - 162 2024.02

Research paper (scientific journal), Joint Work, Accepted

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Drug Repositioning Study on the Antiemetic Efficacy of Anamorelin for Cisplatin-Induced Nausea and Vomiting in Rats

Nishino H†, Kawazoe H†*, Sekiguchi M, Jibiki A, Yokoyama Y, Suzuki S, Nakamura T

BPB Reports (The Pharmaceutical Society of Japan)  7 ( 1 ) 1 - 6 2024.01

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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Objective: Platinum- and anthracycline-based chemotherapy regimens cause nausea and vomiting in clinical practice, resulting in the deterioration of patients’ QoL, discontinuation of chemotherapy, and reduced therapeutic outcomes. Using pica behavior as an indicator, we aimed to clarify whether anamorelin, an orally active ghrelin receptor agonist, exerts antiemetic effects against cisplatin-induced nausea and vomiting in rats.
Materials and methods: Sprague–Dawley rats were treated with cisplatin (5 mg/kg, i.p.), three-drug or four-drug antiemetics (granisetron [0.3 mg/kg, p.o.], dexamethasone [1.5 mg/kg, p.o.], fosaprepitant [12.5 mg/kg, i.p.], with or without anamorelin [30 mg/kg, p.o.]). Data on kaolin intake, normal food intake, and spontaneous motor activity (SMA) were recorded 1 d before and 5 d after cisplatin administration. Body weight (BW) was measured daily, and the percentage change in BW from baseline was calculated.
Results: At the primary endpoint, kaolin intake was significantly higher in the cisplatin-only group than in the pretreatment and vehicle groups (p < 0.05). Additionally, kaolin food intake was not significantly low in cisplatin-treated mice treated with three-drug antiemetics with or without anamorelin. At the secondary endpoints, normal food intake, SMA, and percentage change in BW were significantly lower in the cisplatin-only group than in the vehicle group.
Conclusion: Our findings suggest that the prophylactic administration of standard three-drug antiemetics, besides anamorelin, may not improve cisplatin-induced nausea and vomiting. Further studies using methods suitable for evaluating anamorelin levels are required.

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Influence of menopause on chemotherapy‐induced nausea and vomiting in highly emetogenic chemotherapy for breast cancer: A retrospective observational study

Yokokawa T, Suzuki K, Tsuji D, Hosonaga M, Kobayashi K, Kawakami K, Kawazoe H, Nakamura T, Suzuki W, Sugisaki T, Aoyama T, Hashimoto K, Hatori M, Tomomatsu T, Inoue A, Azuma K, Asano M, Takano T, Ohno S, Yamaguchi M

Cancer Medicine (WILEY)  12 ( 18 ) 18745 - 18754 2023.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2045-7634

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Background: Female sex and younger age are reported risk factors for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy, but the underlying mechanism has not been elucidated. The purpose of this study was to clarify the impact of menopause on CINV.
Methods: This retrospective observational study analyzed data from consecutive patients who received their first cycle of perioperative anthracycline-based chemotherapy for breast cancer between January 2018 and June 2020. The endpoints were association between CINV (vomiting, ≥Grade 2 nausea, complete response [CR] failure) and menopause as well as the association between CINV and follicle-stimulating hormone [FSH]/estradiol [E2].
Results: Data for 639 patients were analyzed. Among these patients, 109 (17.1%) received olanzapine (four antiemetic combinations) and 530 (82.9%) did not (three antiemetic combinations). Premenopausal state (amenorrhea lasting ≥12 months) was significantly associated with ≥Grade 2 nausea and CR failure in univariate analysis but not in multivariate analysis. The premenopausal FSH/E2 group (defined by serum levels; FSH <40 mIU/mL and E2 ≥20 pg/mL) had a significantly higher rate of ≥Grade 2 nausea than the postmenopausal FSH/E2 group (FSH ≥40 mIU/mL and E2 <20 pg/mL) (48.8% vs. 18.8%, p = 0.023).
Conclusions: Our results suggest that changes in FSH and E2 due to menopause may affect the severity of nausea and that FSH and E2 (especially FSH) levels might be useful indicators for CINV risk assessment.

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病院薬剤師のキャリアビジョンに対する意識調査

河添　仁*, 土屋雅美, 藤堂真紀, 原　梓, 大西友美子, 大里洋一, 堀　里子

Yakugaku Zasshi ((公社)日本薬学会)  143 ( 8 ) 683 - 691 2023.08

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  0031-6903

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This study aimed to clarify diverse values toward career visions for hospital pharmacists. A self-administered online questionnaire survey was delivered to live and on-demand release attendees at a symposium about sustainable career paths for pharmacists at the 32nd annual meeting of the Japanese Society of Pharmaceutical Health Care and Sciences between September 23rd and November 14th, 2022. Correspondence analyses of text mining were conducted to assess the association between the participants’ perspectives on career visions and their backgrounds consisting of sex and generation. The recovery rate was 81.9% (136/166). The majority of respondents were women (61.4%), aged ≥40 years (66.1%). Correspondence analysis of career vision for pharmacists showed that respondents who were ≥20–30 years were associated with the research topic, whereas those who were ≥40 years were associated with the director of a pharmacy and worked until retirement age. In contrast, there was no difference in career visions for pharmacists based on sex. The median satisfaction score of the symposium was 6 [interquartile range (IQR): 5–6] in the entire population, as conveyed using a seven-point Likert scale. Interestingly, the median satisfaction scores of the symposium were significantly higher for men in management positions than women in non-management and management positions (p=0.0106 and p=0.0031, respectively). In conclusion, we believe that career support tailored to everyone’s values could enable hospital pharmacists to realize their career visions.

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Clinical and biomarker factors affecting survival in patients with platinum-sensitive relapsed ovarian cancer receiving olaparib monotherapy: a multicenter retrospective study

Tashiro R, Kawazoe H*, Mamishin K, Seto K, Udagawa R, Saito Y, Hashimoto H, Shimoi T, Yonemori K, Yonemura M, Terakado H, Nishimura T, Kawasaki T, Furukawa T, Nakamura T

Scientific Reports (NATURE PORTFOLIO)  13   11962 2023.07

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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The standard treatment for platinum-sensitive relapsed ovarian cancer (PSROC) is platinum-based chemotherapy followed by olaparib monotherapy. A retrospective study was conducted to identify factors affecting the survival of patients with PSROC undergoing olaparib monotherapy in real-world clinical settings. The study enrolled 122 patients who received olaparib monotherapy between April 2018 and December 2020 at three national centers in Japan. The study used the Kaplan–Meier method and univariable and multivariable Cox proportional hazards models to evaluate the associations between factors and progression-free survival (PFS). Patients with BRCA1/2 mutations had a significantly longer median PFS than those without these mutations. Both the BRCA1/2 mutation-positive and mutation-negative groups exhibited a prolonged PFS when the platinum-free interval (PFI) was ≥ 12 months. Cancer antigen 125 (CA-125) level within reference values was significantly linked to prolonged PFS, while a high platelet-to-lymphocyte ratio (≥ 210) was significantly associated with poor PFS in the BRCA1/2 mutation-negative group. The study suggests that a PFI of ≥ 12 months may predict survival after olaparib monotherapy in patients with PSROC, regardless of their BRCA1/2 mutation status. Additionally, a CA-125 level within reference values may be associated with extended survival in patients without BRCA1/2 mutations. A larger prospective study should confirm these findings.

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実務実習終了時における到達度評価を向上させる要因は何か？

石川春樹, 河添　仁*, 岩田紘樹, 中村友紀, 地引　綾, 横山雄太, 小林典子, 鈴木小夜, 山浦克典, 中村智徳

医療薬学 ((一社)日本医療薬学会)  49 ( 4 ) 173 - 182 2023.04

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  1346-342X

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2021年度の当大学薬学部の5年次生146名を対象に、実務実習事前学習の学業成績を調査し、実務実習における到達度評価の向上に関わる因子を評価した。146名の実務実習事前学習の学業成績は81.2±2.0点、最大値は86.0点、最小値は74.0点であった。平均値で本学が目標とするスコア3に到達していた項目は薬局実習では10項目中6項目、病院実習では11項目中4項目であり、薬局実習よりも病院実習で目標到達率が低かった。なかでも、「処方箋に基づく調剤」のうち「患者情報の把握」はスコア3以上に到達していた実習生が146人中85人(38.2%)と目標到達率の低い項目であった。今回の検討から、代表的8疾患への関わりを増やすことで到達度評価を向上させる可能性が示唆された。すなわち、少数の患者であっても代表的8疾患に幅広く関わりを経験させる目標を優先させた方が実習生の到達度評価が向上することが示された。

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Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study

Nasu I, Kondo M, Uozumi R, Takada S, Nawata S, Iihara H, Okumura Y, Takemoto M, Mino K, Sasaki T, Hirose C, Aomori T, Shimano R, Maeno K, Oizumi S, Kusumoto S, Ohno Y, Ikemura S, Takai D, Hara A, Kawazoe H*, Nakamura T

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER)  14 ( 5 ) 676 - 688 2023.03

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  1837-9664

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Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet.
Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression β coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed.
Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648.
Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

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Ingenol mebutate inhibits the growth of pancreatic cancer cells in vitro via STING with an efficacy comparable to that of clinically used anticancer agents

Kikuyama F, Suzuki S, Jibiki A, Yokoyama Y, Kawazoe H, Kitanaka S, Nakamura T

Journal of Natural Medicines (SPRINGER)  77   343 - 351 2023.01

Research paper (scientific journal), Joint Work, Accepted

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Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC50 values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.

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Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small cell Lung Cancer: a Prospective Observational Study

Ishikawa E, Yokoyama Y, Chishima H, Kasai H, Kuniyoshi O, Kimura M, Hakamata J, Nakada H, Suehiro N, Nakaya N, Nakajima H, Ikemura S, Kawada I, Yasuda H, Terai H, Jibiki A, Kawazoe H, Soejima K, Muramatsu H, Suzuki S, Nakamura T

Investigational New Drugs (SPRINGER)  41   122 - 133 2023.01

Research paper (scientific journal), Joint Work, Accepted

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Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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Patient-associated risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy: A multicenter retrospective study

Tashiro R, Kawazoe H*, Mamishin K, Seto K, Udagawa R, Saito Y, Hashimoto H, Shimoi T, Yonemori K, Yonemura M, Terakado H, Kawasaki T, Furukawa T, Nakamura T

Frontiers in Oncology (FRONTIERS MEDIA SA )  12   898150 2022.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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Background: Olaparib-induced anemia is a frequently occurring complication in patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and is associated with a marked deterioration in patients’ health-related quality of life. This study aimed to clarify patient-specific risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy in a real-world setting.

Methods: This multicenter, retrospective, observational study enrolled consecutively presenting patients with advanced ovarian or breast cancer who received olaparib monotherapy as maintenance or palliative treatment between April 2018 and December 2020 at three participating medical institutions in Japan. The primary endpoint was patient-associated risk factors underlying the onset of grade ≥3 anemia from olaparib treatment initiation to 90 days after treatment. Receiver operating characteristic curves were constructed and univariable and multivariable logistic regression analyses were performed to evaluate the association between patient-associated risk factors and grade ≥3 anemia.

Results: Of 113 patients evaluated in this study, 32.7% (n = 37) had grade ≥3 anemia. Multivariable logistic regression analysis revealed that low baseline red blood cell (RBC) count (<3.3 × 106 cells/μL), low baseline hematocrit level (<35%), low baseline hemoglobin level (<11.6 g/dL), and breast cancer susceptibility (BRCA1/2) mutation were significantly associated with the onset of grade ≥3 anemia (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 1.28–9.62; P = 0.017, adjusted OR, 3.63; 95% CI, 1.28–11.64; P = 0.021, adjusted OR, 3.89; 95% CI, 1.39–12.21; P = 0.014, and adjusted OR, 4.09; 95% CI, 1.55–11.67; P = 0.006, respectively).

Conclusions: Our findings suggest that low baseline RBC count, low baseline hematocrit level, and low baseline hemoglobin level might be the patient-associated risk factors for severe anemia induced by olaparib monotherapy. Additionally, BRCA1/2 mutation was suggested to be a patient-related risk factor for anemia regardless of severity. Therefore, applying these patient-associated risk factors would help classify and screen patients at risk of severe anemia.

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Vonoprazan-associated nephrotoxicity: extensive real-world evidence from spontaneous adverse drug reaction reports

Ishida M, Tsuchiya M, Naito J, Kawazoe H, Watanabe D, Nonaka Y, Sano M, Sakai H, Suzuki A, Kumada K, Okura H, Shimizu M, Iihara H

Kidney International (ELSEVIER)  102 ( 3 ) 666 - 668 2022.09

Research paper (scientific journal), Joint Work, Accepted

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Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography–Photodiode array detection

Yokoyama Y, Nozawa E, Morita M, Ishikawa E, Mori T, Sakurai M, Kikuchi T, Matsuki E, Yamazaki R, Kataoka K, Jibiki A, Kawazoe H, Suzuki S, Nakamura T

Journal of Clinical Laboratory Analysis (WILEY)  36 ( 8 ) e24598 2022.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0887-8013

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Background

Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs.
Methods

Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system.
Results

The calibration ranges were 2–500 ng/ml for dasatinib, 100–5000 ng/ml for nilotinib, and 10–500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%–96.0%, 80.7%–86.1%, 91.6%–99.0%, and 86.4%–92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively.
Conclusion

To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

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Association between the Co-administration of Histamine H2 Receptor Antagonists and the Effectiveness of Capecitabine in Patients with Colorectal Cancer: Propensity Score Analysis

Yamazaki T, Uozumi R, Kawazoe H*, Kitazume Y, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yoshizawa T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Furukawa T

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER)  13 ( 10 ) 3073 - 3083 2022.08

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  1837-9664

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Background: The association between the effectiveness of capecitabine and the concomitant administration of gastric acid suppressants remains controversial. We aimed to clarify whether the effectiveness of capecitabine is affected by the co-administration of histamine H2 receptor antagonists (H2RAs) in early-stage colorectal cancer (CRC) patients using real-world data.
Methods: This multicenter, retrospective, observational study included consecutive patients with stage II-III CRC who received either capecitabine monotherapy or the CapeOX regimen (capecitabine and oxaliplatin) as adjuvant therapy between January 2009 and December 2014 in Japan. Relapse-free survival (RFS) and overall survival were estimated using the Kaplan-Meier method. Additionally, multivariable Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting analyses were performed.
Results: In total, 552 patients were included in this study, of which 30 were co-administered H2RAs. RFS at five years was 76.7% (95% confidence interval [CI]: 57.2-88.1%) and 79.8% (95% CI: 76.0-83.0%) in the H2RA and non-H2RA groups, respectively. Multivariable Cox proportional hazards model and propensity score-adjusted analyses showed that the co-administration of H2RAs was associated with a poor RFS among those receiving capecitabine monotherapy (hazard ratio [HR], 2.01; 95% CI: 0.86-4.70 and HR, 1.81; 95% CI: 0.77-4.22, respectively). In contrast, these results were inconsistent with the group receiving the CapeOX regimen.
Conclusions: The study findings suggest that the co-administration of H2RAs may not reduce the effectiveness of capecitabine therapy in patients with early-stage CRC. To confirm this relationship, a prospective study with a pharmacokinetic approach is needed.

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多様な進路・働き方における薬剤師のキャリアパスに対する意識調査

土屋雅美†, 河添　仁†*, 大西友美子, 島田美樹, 堀　里子

医療薬学 ((一社)日本医療薬学会)  48 ( 6 ) 249 - 258 2022.06

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  1346-342X

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This study aimed to clarify the attitudes toward career paths for pharmacists in Japan. A self-administered online questionnaire survey was delivered to the live and on-demand release attendees at the 31st annual meeting of the Japanese Society of Pharmaceutical Health Care and Sciences between October 14th and December 7th, 2021. A customer satisfaction (CS) analysis was performed to assess the association between the participants’ perspectives on career paths and satisfaction. The recovery rate was 90.3％ (65/72). The number of females and males was 57 and 8, respectively. The respondents were from diverse backgrounds of age, workplace, and position, etc. The median satisfaction scores of job, education & training system, research activities, relationships, management’s consideration of women, the presence of role models, salary, career path support by colleagues, career path support by supervisors, career path support by a family member, work-life balance, and career paths was 4 (interquartile range [IQR]: 3 - 5), 3 (IQR: 2 - 4), 3 (IQR: 2 - 4), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 2 (IQR: 1 - 4), 4 (IQR: 2 - 5), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 5 (IQR: 5 - 7), 4 (IQR: 3 - 5), and 4 (IQR: 3 - 5), respectively. CS analysis revealed that the education & training system, work-life balance, and research activities should be improved as a matter of highest priority for a career path. In conclusion, the findings may provide useful information to develop career paths for Japanese pharmacists in diverse careers and work styles in the future.

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薬学生の自己理解を支援する性格検査MBTI®研修会とそのアウトカム

河添　仁*, 大里洋一

医療薬学 ((一社)日本医療薬学会)  48 ( 5 ) 218 - 227 2022.05

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  1346-342X

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We newly introduced an on-site workshop of personality inventory, using the Myers-Briggs Type Indicator® (MBTI®) intended for pharmacy students in January 2022. The aim of this study was to evaluate the outcome of the MBTI® workshop to support pharmacy studentsʼ self-understanding via an online questionnaire survey. All third- to ?fth-year students of the Keio University Faculty of Pharmacy (n = 17) assessed the self-understanding, clarity of career path, and their own MBTI® type during the pre-workshop phase, and after the lecture of MBTI®, personality inventory of the MBTI®, and the MBTI® workshop. The recovery rate of the questionnaire was 100％. Notably, the self-guessed MBTI® typeafter the lecture of MBTI® was different from that after the personality inventory of the MBTI® and the MBTI® workshop (94.1％ and 88.2％, respectively). Respondents showed positive scores after participating in the workshop, compared with those before, as conveyed through the use of a seven-point Likert scale. The median scores of self-understanding and clarity of career path after participating in the workshop were signi?cantly improved from 5 (interquartile range [IQR]: 3.5 - 5.5) to 6 (IQR: 6 - 6) and 4 (IQR: 2 - 5) to 5 (IQR: 4 - 6), respectively. They also expressed high overallsatisfaction on the workshop (median 7 [IQR: 6.5 - 7]). In conclusion, this study demonstrated the usefulness of the MBTI® workshop as an educational program to support pharmacy studentsʼ self-understanding. The evaluation of their career path after the MBTI® workshop is warranted in the future.

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Proton pump inhibitors affect capecitabine efficacy in patients with stage II–III colorectal cancer: a multicenter retrospective study

Kitazume Y, Kawazoe H*, Uozumi R, Yoshizawa T, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yamazaki T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Yamaguchi M

Scientific Reports (NATURE PORTFOLIO)  12   6561 2022.04

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II–III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan–Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22–5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II–III CRC.

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