論文 - 地引　綾

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 （Pharmacotherapy）  44 （ 2 ） 149 - 162 2023年11月

ISSN  02770008

　概要を見る

Study Objective: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum β-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients. Design: Prospective observational study. Patients: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. Measurements: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration. Setting: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR) with measured body weight (BW) using the Cockcroft–Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. Main Results: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CLCR) using the Cockcroft–Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L. Conclusions: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients.

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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 （一般社団法人　日本医療薬学会）  49 （ 4 ） 173 - 182 2023年04月

研究論文（学術雑誌）, 共著, 査読有り

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 （Journal of Natural Medicines）  77 （ 2 ） 343 - 351 2023年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13403443

　概要を見る

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 （Investigational New Drugs）  41 （ 1 ） 122 - 133 2023年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01676997

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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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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 （Journal of Clinical Laboratory Analysis）  36 （ 8 ）  2022年08月

ISSN  08878013

　概要を見る

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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Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

Ishikawa E., Yokoyama Y., Chishima H., Kuniyoshi O., Sato I., Nakaya N., Nakajima H., Kimura M., Hakamata J., Suehiro N., Nakada H., Ikemura S., Jibiki A., Kawazoe H., Muramatsu H., Suzuki S., Nakamura T.

Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences （Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences）  1199 2022年05月

ISSN  15700232

　概要を見る

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 μL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5–125.0 ng/mL for afatinib, 2.5–125.0 ng/mL for dacomitinib, 4.0–800.0 ng/mL for osimertinib, 1.0–125.0 ng/mL for AZ5104, and 2.5–125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

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Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study

Ogiwara T., Kawazoe H., Egami S., Hashimoto H., Saito Y., Sakiyama N., Ohe Y., Yamaguchi M., Furukawa T., Hara A., Hiraga Y., Jibiki A., Yokoyama Y., Suzuki S., Nakamura T.

Frontiers in Oncology （Frontiers in Oncology）  11 2021年11月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Background: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. Methods: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. Results: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. Conclusions: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

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Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice

Sekiguchi M., Sagano N., Kawazoe H., Hiraga Y., Jibiki A., Yokoyama Y., Suzuki S., Nakamura T.

Pharmazie （Pharmazie）  76 （ 10 ） 484 - 487 2021年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00317144

　概要を見る

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups (p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

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薬学教育モデル・コアカリキュラムに基づく実務実習におけるルーブリック形式の概略評価は実習生のパフォーマンスレベルを評価できるか？

河添　仁, 鈴木小夜, 平賀ゆい, 横山雄太, 地引 綾, 岩田紘樹, 小林典子, 藤本和子, 中田英夫, 青森　達, 山浦克典, 中村智徳, 村松　博, 青森　達, 望月眞弓

医療薬学 （一般社団法人　日本医療薬学会）  47 （ 9 ） 513 - 524 2021年09月

研究論文（学術雑誌）, 共著, 査読有り

院内製剤の抗微生物薬，抗ウイルス薬，塩化ナトリウム点眼薬の長期保存における安定性の評価

武田真美, 横山雄太, 渡邉武明, 平賀ゆい, 地引 綾, 河添　仁, 鈴木小夜, 門田佳子, 中村智徳

医療薬学 （日本医療薬学会）  47 （ 6 ） 316 - 325 2021年06月

研究論文（学術雑誌）, 共著, 査読有り

代表的8疾患と薬局実習が病院実習の到達度に与える影響

清宮 啓介, 津田壮一郎, 池淵由香, 鈴木小夜, 地引 綾, 岩田紘樹, 横山雄太, 河添　仁, 小林典子, 藤本和子, 山浦克典, 中村智徳, 村松　博, 青森　達, 望月眞弓

医療薬学 （一般社団法人　日本医療薬学会）  46 （ 12 ） 715 - 721 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

実務実習生の薬学専門科目に対する自己効力感は実務実習での成功体験に影響を与える

菊山史博, 鈴木小夜, 地引 綾, 横山雄太, 河添　仁, 中村智徳

薬学雑誌 （日本薬学会）  140 （ 6 ） 799 - 808 2020年06月

研究論文（学術雑誌）, 共著, 査読有り

デキサメタゾン配合後における先発及び後発品のゲムシタビン注射剤の製剤学的安定性の評価

吉浦誠海, 河添　仁, 鈴木小夜, 横山雄太, 地引 綾, 中村智徳

日本臨床腫瘍薬学会雑誌 （日本臨床腫瘍薬学会）  14   1 - 7 2020年04月

研究論文（学術雑誌）, 共著, 査読有り

改訂薬学教育モデル・コアカリキュラムに準拠した実務実習に向けたルーブリック形式の概略評価を用いたパフォーマンス評価の先行導入：学生視点に基づくアウトカム評価と教育効果向上のための提案

鈴木小夜，河添　仁，地引　綾，横山雄太，中村智徳

医療薬学 45 （ 4 ） 228 - 239 2019年04月

研究論文（学術雑誌）, 共著, 査読有り

Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis

Tohru Aomori, Ayumi Tsuchiya, Sayo Suzuki, Aya Jibiki, Naoko Otsuka, Eriko Ishioka, Yuko Kaneko, Tsutomu Takeuchi, Tomonori Nakamura

Die PHARMAZIE 72   95 - 97 2017年

研究論文（学術雑誌）, 共著, 査読有り

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Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment

Ayumi Tsuchiya, Tohru Aomori, Mami Sakamoto, Arisa Takeuchi, Sayo Suzuki, Aya Jibiki, Naoko Otsuka, Eriko Ishioka, Yuko Kaneko, Tsutomu Takeuchi, Tomonori Nakamura

Die PHARMAZIE 72   22 - 28 2017年

研究論文（学術雑誌）, 共著, 査読有り

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電子味覚システムとヒト官能試験によるクリンダマイシンの苦味抑制飲食物の探索

高木彰紀，久保理絵，地引　綾，青森　達，鈴木小夜，中村智徳

医療薬学 43 （ 9 ） 492 - 501 2017年

研究論文（学術雑誌）, 共著, 査読有り

事前学習および薬局実習における OTC 実習の問題点と満足度向上のための提案

栗原 智香, 青森 達, 鈴木 小夜, 高木 彰紀, 大塚 尚子, 地引 綾, 中村 智徳

薬学教育 （薬学教育学会）  １ 2017年

研究論文（学術雑誌）, 共著, 査読有り

膠原病患者におけるグルココルチコイド製剤による副作用発現に関する実態調査

中島 綾, 土岐浩介, 本間真人, 寒河江照美, 齋藤玲子, 伊藤 聡, 住田孝之, 幸田幸直

藥学雑誌 （日本薬学会）  129 （ 4 ） 445 - 450 2009年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0031-6903

Analysis of correlation between prescription drugs for climacteric disorders and CA repeat polymorphism of estrogen receptor β gene

根岸悦子, 竹尾愛梨, 中島 綾, 久光健一, 天野恵子, 平井愛山, 上野光一

医療薬学 （日本医療薬学会）  32 （ 1 ） 21 - 26 2006年01月

研究論文（学術雑誌）, 共著, 査読有り

Association of cytosine-adenine repeat polymorphism of the estrogen receptor-beta gene　with menopausal symptoms

Takeo C., Negishi E., Nakajima A., Ueno K., Tatsuno I., Saito Y., Amano K., Hirai A.

Gender Medicine 2 （ 2 ） 96 - 105 2005年06月

研究論文（学術雑誌）, 共著, 査読有り