研究者詳細 - 今井　俊吾

AIM: Dosage adjustment is essential in older individuals because they are prone to experience a decline in liver function and changes in body composition. However, quantitative tests or equations for evaluating the activity of hepatic drug metabolism have not yet been clearly established. We examined hepatic drug metabolism activities in older individuals, focusing on changes in body composition parameters. METHODS: Lansoprazole and nifedipine, substrates of the metabolic enzymes cytochrome P450 (CYP) 2C19 and 3A4, respectively, were selected to study hepatic drug metabolism. Residual samples from blood test for older patients were evaluated to determine drug metabolism. The body composition of relevant patients was determined by analyzing characteristic parameters of skeletal muscle mass index (SMI), handgrip strength (HGS) and hepatic steatosis index (HSI). The differences in hepatic drug metabolism were studied statistically among categories in terms of the cut-off value of these parameters. RESULTS: Older male patients receiving lansoprazole and nifedipine in the low SMI (<7.0 kg/m2 ) category showed an 85-90% reduction in respective CYP2C19 and CYP3A4 metabolic activities compared with the normal SMI category. For the female patients, CYP2C19 and CYP3A4 metabolic activities showed no significant correlation with SMI and HGS. Fatty liver disease (HSI ≥36) was found to reduce CYP2C19 metabolic activity particularly in older female patients. CONCLUSIONS: Low CYP2C19 metabolic activity was statistically correlated with low SMI in male patients and high HSI in female patients, whereas low CYP3A4 metabolic activity was statistically correlated with low HGS in male patients.

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Using Japanese big data to investigate novel factors and their high-risk combinations that affect vancomycin-induced nephrotoxicity.

Shungo Imai, Shota Kadomura, Takayuki Miyai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

British journal of clinical pharmacology 88 （ 7 ） 3241 - 3255 2022年02月

研究論文（学術雑誌）, 筆頭著者, 責任著者, 査読有り

AIMS: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. METHODS: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine ≥0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. RESULTS: Of the 7,306 patients that were enrolled, VIN occurred in 14.2% of them (1,035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio; 0.701, 95% confidence interval; 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM <7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations ≥20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. CONCLUSIONS: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

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Clinical applicability of urinary creatinine clearance for determining the initial dose of vancomycin in critically ill patients.

Ryusei Mikami, Shungo Imai, Mineji Hayakawa, Mitsuru Sugawara, Yoh Takekuma

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 （ 2 ） 199 - 205 2022年02月

研究論文（学術雑誌）, 査読有り

INTRODUCTION: The purpose of this study was to evaluate the clinical applicability of urinary creatinine clearance (CrCl) for determining the initial dose of vancomycin (VCM) in critically ill patients and to assess VCM trough plasma concentration/maintenance daily dose (C/D) ratio in patients with augmented renal clearance (ARC). METHODS: As the primary outcome measure, correlations between estimated renal function and the VCM C/D ratio were compared using the following formulas: CrCl, Cockcroft-Gault equation (eCrClC-G) and KineticGFR equation (KeGFR). Patients were divided into those with or without changes in renal function. The patients were further classified based on the presence or absence of ARC. The secondary outcome was the comparison of VCM C/D ratio between ARC and Non-ARC patients. RESULTS: A total of 65 patients were enrolled for analysis. In all groups, CrCl tended to correlate better with the VCM C/D ratio than eCrClC-G and KeGFR. A significantly lower VCM C/D ratio was observed in patients with persistent ARC than in the Non-ARC group (0.24 versus 0.52 kg/L). CONCLUSIONS: The clinical applicability of CrCl for the initial dosing design of VCM in critically ill patients was shown. Furthermore, the results indicated that patients with persistent ARC required a higher VCM dose than Non-ARC patients. Although our findings are limited, they have a value for further verification.

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Investigation of the risk factors of vomiting during linezolid therapy: a retrospective observational study.

Takezo Tsutsumi, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

European journal of clinical pharmacology （Springer Science and Business Media LLC） 78 （ 2 ） 279 - 286 2022年02月

研究論文（学術雑誌）, 査読有り, ISSN 0031-6970

PURPOSE: Some clinical studies have reported the occurrence of nausea and vomiting with linezolid (LZD) administration. However, no studies have evaluated nausea and vomiting as primary endpoints. In a previous study, we noted a possible relationship between LZD and vomiting, but risk factors were not identified. Therefore, the aim of the present study was to identify them. METHODS: Patients who received LZD 600 mg twice daily at Hokkaido University Hospital from September 2008 to April 2019 were enrolled in this retrospective observational study. Patient characteristics, concomitant medications, laboratory data, and the occurrence of vomiting were obtained from electronic medical records. Logistic regression analysis was performed to identify risk factors for vomiting, including age, sex, body weight, concomitant medications, and surgeries. RESULTS: A total of 496 patients were included in this study, of which 90 experienced vomiting. By multivariate logistic regression analysis, female sex (adjusted odds ratio [aOR], 2.69; 95% confidence interval [CI], 1.62-4.47), ≥ 10 days of LZD administration (aOR, 2.57; CI, 1.46-4.50), and hyponatraemia (aOR, 2.96; CI, 1.72-5.10) were identified as independent risk factors for vomiting; administration of serotonergic agents (aOR, 0.23; CI, 0.07-0.82) was negatively associated. CONCLUSIONS: This study is the first to successfully identify risk factors for LZD-induced vomiting. Careful monitoring of patients with these risk factors may lead to safer and sustainable LZD administration.

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Prescription and therapeutic drug monitoring status of valproic acid among patients receiving carbapenem antibiotics: A preliminary survey using a Japanese claims database

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Annals of Clinical Epidemiology （Society for Clinical Epidemiology） 4 （ 1 ） 6 - 10 2022年01月

研究論文（学術雑誌）, 筆頭著者, 査読有り

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薬局薬剤師を対象としたメディアによる「くすりの危険性」に関する報道に起因する患者からの相談応需の実態調査

今井俊吾, 阿部真也, 松井洸, 柏木仁, 佐藤夕紀, 武隈洋, 吉町昌子, 菅原満

医薬品情報学 24 （ 2 ） 75 - 87 2022年

研究論文（学術雑誌）, 筆頭著者, 責任著者, 査読有り

週刊誌に掲載された「危ないクスリ」に関する情報の整理とその適切性評価

今井俊吾, 柏木仁, 佐藤夕紀, 武隈洋, 菅原満

医薬品情報学 24 （ 1 ） 1 - 10 2022年

研究論文（学術雑誌）, 筆頭著者, 責任著者, 査読有り

大規模レセプトデータベースを用いた臨床研究

武隈洋, 今井俊吾, 菅原満

藥学雜誌（Pharmaceutical Society of Japan） 142 （ 4 ） 331 - 336 2022年

研究論文（その他学術会議資料等）, ISSN 0031-6903

The JMDC Claims Database® contains completely anonymized receipt information on the insured members of health insurance associations. The number of registered users is approximately 9.6 million (6% of the population) as of May 2020. In this database, it is possible to track even outpatient treatment, even if the patient changes the medical facility, as long as the insurer of the subscriber's health insurance does not change, so that long-term medical treatment could be targeted as a research theme. However, as the data do not contain medical record information, it is not possible to obtain laboratory values, although it is possible to know whether clinical tests have been performed. For pharmaceutics-related research, the most suitable use of the receipt database like JMDC Claims Database® seems to be the investigation of actual prescriptions. However, the research topics that pharmacists are interested in are probably comparisons of drug effects, drug-drug interactions, or causal analysis of drugs and side effects. However, laboratory data for evaluating drug efficacy is not available in the receipt database, and the accuracy of the disease name in the database becomes problematic when using the disease name as information indicating the occurrence of side effects. In this review, we introduce our studies performed by using JMDC Claims Database® and how to manage the above-described problems. We hope that this study will be helpful to those who are going to engage in research using medical big data.

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オンライン会議システムを活用した医療面接実習の実践とその評価

森綾子, 加藤いづみ, 柏木仁, 今井俊吾, 鳴海克哉, 佐藤夕紀, 古堅彩子, 山田勇磨, 小林正紀

薬学雑誌 142 （ 6 ） 661 - 774 2022年

研究論文（学術雑誌）, 査読有り

Performance Status 不良群におけるナルデメジンの有効性の検証

加藤信太郎, 齋藤佳敬, 小野田紘子, 熊井正貴, 今井俊吾, 敦賀健吉, 武隈洋, 菅原満

薬学雑誌 142 （ 7 ） 755 - 760 2022年

研究論文（学術雑誌）, 査読有り

Evaluation of the strategies to reduce third-generation oral cephalosporins in dentistry at a Japanese academic hospital: An interrupted time series analysis

Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi

Journal of Clinical Pharmacy and Therapeutics 47 （ 7 ） 1010 - 1019 2022年

研究論文（学術雑誌）, 査読有り

WHAT IS KNOWN AND OBJECTIVE: Third-generation oral cephalosporins, especially cefcapene-pivoxil (CFPN-PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost-effectiveness of antibiotics. METHODS: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). RESULTS AND DISCUSSION: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN-PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). WHAT IS NEW AND CONCLUSION: After December 2014, prophylactic antibiotics were switched from CFPN-PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost-effectiveness perspective.

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Development of a method of liquid chromatography coupled with tandem mass spectrometry for simultaneous determination of linezolid and tedizolid in human plasma

Yuki Sato, Yoh Takekuma, Takayuki Daisho, Hitoshi Kashiwagi, Shungo Imai, Mitsuru Sugawara

Biological and Pharmaceutical Bulletin 45 （ 4 ） 421 - 428 2022年

研究論文（学術雑誌）, 査読有り

It is important to select appropriate antibiotics for infection control. Linezolid and tedizolid are newly developed and synthesized oxazolidinone antibacterial agents. It has been pointed out that there is a relationship between a high plasma concentration of the target drug and incidence of adverse effects, although it has been reported that neither linezolid nor tedizolid requires dose adjustment according to renal function. Due to the high incidence of adverse effects, both are often switched. Precise plasma concentration control by therapeutic drug monitoring (TDM) is desirable for reducing the adverse effects of both drugs and obtaining a better therapeutic effect. In this study, we aimed to establish a method for simultaneous quantification of linezolid and tedizolid in human plasma using LC coupled with tandem mass spectrometry. Sample preparation was performed by a simple operation with acetonitrile. Linezolid and tedizolid were separated by an octadecylsilyl column using a gradient elution of acetonitrile in aqueous 0.1% formic acid solution and were detected in the positive ion electrospray mode with multiple reaction monitoring. Quantification of linezolid and tedizolid ranged from 0.5 to 50 and 0.5 to 20 µg/mL, respectively. The intra-day and inter-day precision and accuracy of data were assessed and found to be acceptable. The developed method was successfully applied to measurement of the concentrations of linezolid and tedizolid. This simple method, which can simultaneously quantify both drug concentrations for daily TDM, could contribute to safer treatment of patients.

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Machine learning-based model for estimating vancomycin maintenance dose to target the area under the concentration curve of 400-600 mg・h/L in Japanese patients

Takayuki Miyai, Shungo Imai, Eri Yoshimura, Hitoshi Kashiwagi, Yuki Sato, Hidefumi Ueno, Yoh Takekuma, Mitsuru Sugawara

Biological and Pharmaceutical Bulletin 45 （ 9 ） 1332 - 1339 2022年

研究論文（学術雑誌）, 責任著者, 査読有り

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

Shota Kadomura, Shungo Imai, Kenji Momo, Yuki Sato, Hitoshi Kashiwagi, Tatsuya Itoh, Mitsuru Sugawara, Yoh Takekuma

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners 10781552211034703 - 10781552211034703 2021年10月

研究論文（学術雑誌）, 査読有り

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

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A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Expert opinion on drug safety 20 （ 10 ） 1257 - 1266 2021年10月

研究論文（学術雑誌）, 筆頭著者, 査読有り

BACKGROUND: Hypernatremia and liver injury are typical adverse effects of tolvaptan. Therefore, hospitalization and frequent monitoring of serum sodium concentration and liver function are necessary for tolvaptan initiation. We performed a cross-sectional survey to evaluate these situations. RESEARCH DESIGN AND METHODS: We employed the Japanese claims database, which contains data of patients aged < 75 years. Patients who were newly prescribed tolvaptan for fluid accumulation induced by chronic heart failure (FA-CHF) or liver cirrhosis (FA-LC) from January 2011 to June 2017 were included. We evaluated the hospitalization status and implementation of serum sodium and liver function tests in the evaluation period, based on the Japanese package insert. RESULTS: Of 1,173 patients, 347 and 117 were enrolled in FA-CHF and FA-LC groups, respectively. Among them, 10.7% (FA-CHF group) and 5.13% (FA-LC group) were prescribed tolvaptan without hospitalization. In the FA-CHF group, 11.0% and 17.6% did not undergo serum sodium and liver function tests even once in the evaluation period, respectively, compared with 12.0% and 12.8% in the FA-LC group. CONCLUSIONS: Our results highlight the deviation from Japanese package insert recommendations. This approach can be applied to other drugs and provides important perspectives on pharmacovigilance research.

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Factors affecting creatine phosphokinase elevation during daptomycin therapy using combination of machine learning and conventional methods.

Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

British journal of clinical pharmacology 88 （ 3 ） 1211 - 1222 2021年08月

研究論文（学術雑誌）, 筆頭著者, 責任著者, 査読有り

AIMS: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. METHODS: A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and > 200 IU/L, and (2) > 1,000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree (DT) analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. RESULTS: Of the 2,970 patients who received DAP, 706 were included. Elevation of CPK values > 200 IU/L and > 1,000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In DT analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. CONCLUSIONS: Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

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レセプトデータに基づくクローン病新規ブデソニド徐放性製剤の実態調査

窪田篤人, 今井俊吾, 百賢二, 菅原満, 武隈洋

薬局薬学（(一社)日本薬局学会） 13 （ 1 ） 54 - 61 2021年04月

研究論文（学術雑誌）, 査読有り, ISSN 1884-3077

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今井　俊吾

論文 - 今井　俊吾