KASAI Hidefumi



Keio Frontier Research & Education Collaborative Square (K-FRECS), K-FRECS at Tonomachi (Mita)


Project Associate Professor (Non-tenured)

Contact Address

35 Shinanomachi, Shinjuku-ku, Tokyo

Career 【 Display / hide

  • 2002.04

    Keio University, School of Medicine, Project Instructor

  • 2018.11

    Keio University, School of Medicine, Project Instructor

Academic Background 【 Display / hide

  • 1987.04

    The University of Tokyo, Faculty of Science, Department of Biochemistry

    University, Graduated, Other


Research Areas 【 Display / hide

  • Life Science / Clinical pharmacy (Pharmacometrics)

Research Keywords 【 Display / hide

  • PK/PD

  • pharmacometrics

  • clinical pharmacology


Papers 【 Display / hide

  • Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer

    Tsushima T., Kasai H., Tanigawara Y.

    Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology)  86 ( 4 ) 487 - 495 2020.10

    ISSN  03445704

     View Summary

    © 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer. Methods: PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125 mg/m2) or every 3 weeks (200, 260, or 300 mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts. Results: The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts. Conclusion: We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

  • 母集団薬物動態解析のための採血デザイン検討ツールの開発

    鈴木 萌子, 笠井 英史, 佐古 兼一

    TDM研究 ((一社)日本TDM学会)  36 ( 3 ) 81 - 95 2019.09

    ISSN  0911-1026

     View Summary

    ベイズ法による個別投与設計においては、良質な母集団解析結果、ひいては、そのための試験デザインが最も重要となる。そこで、今回、設定した試験デザインの質を簡便に検討する目的でシミュレーションツールを開発した。使用者は採血の実施可能性に対応しsampling cost scoreを設定し、統計学的要請とのバランスを考慮して試験デザインを検討できるようにした。Sampling cost scoreは、施設の事情や解析の目的に応じて使用者が任意に与えることとした。既報のバンコマイシンの母集団薬物動態モデルを用いて、0.25-24時間の任意の各時点に患者当たり1点から4点採血したデータを発生させ、そのデータに対して薬物動態パラメータの推定を100回実施した。試験デザインの優劣は、解析成功率、パラメータ推定値のバイアス、および、sampling cost scoreとの総合的考察で判断した。解析ソフトはPhoenix NLME Version 7.0(Certara、Princeton、NJ、USA)を用いた。作成したツールを用いて検討した結果、解析成功率は採血数およびサンプルサイズに依存し、また、パラメータ推定値のバイアスが少ないデザインは、sampling cost scoreが相対的に大きくなることが明らかとなった。開発したツールは母集団解析の試験デザインの実践に、また、その考え方を習得するための教育ツールとしてもきわめて有用である。(著者抄録)

  • 成人がん患者における好中球減少の影響を考慮したバンコマイシンの母集団薬物動態解析

    鈴木 萌子, 笠井 英史, 佐古 兼一, 清水 裕, 織本 桂, 矢吹 直寛, 渡邊 なお子, 丸林 万希子, 中村 益美, 駒井 信子, 渡邉 好造

    TDM研究 ((一社)日本TDM学会)  36 ( 3 ) 96 - 104 2019.09

    ISSN  0911-1026

     View Summary

    がん患者におけるバンコマイシンの母集団薬物動態解析を実施した。がん患者144例および非がん患者102例の計246例から得た433ポイントのうち95%以上がトラフ値であり、全ての薬物動態パラメータを同時に精度よく推定することは不可能であったため、2-コンパートメントモデルを用いてクリアランス(CL)のみ解析した。CLに対しては血清クレアチニン(SCR)、年齢(AGE)、除脂肪体重(LBW)および好中球数減少(<500/μL)の有無が有意な共変量として見出され、Final modelは、CL(L/hr)=2.70×(SCR/0.67)-0.828×(AGE/71.5)-0.780×(LBW/42.6)1.28×(1.32×eη1)Neut×(eη2)(1-Neut)となった[Neut:好中球数<500/μL=1、≧500/μL=0]。すなわち、好中球減少によってCLが通常の1.32倍に亢進することが示された。既存モデルを用いて投与設計を行うとCLが過小評価され、その結果、投与量が過小となる恐れがあるが、本モデルを用いることで早期に有効濃度域に到達させることが可能となり、今回得られた母集団パラメータは成人がん患者の投与設計に有用であると考えられる。(著者抄録)

  • Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms

    Yamaguchi D., Tsuji Y., Sonoda M., Shin K., Kito H., Ogami C., Kasai H., To H., Kamimura H.

    European Journal of Drug Metabolism and Pharmacokinetics (European Journal of Drug Metabolism and Pharmacokinetics)  44 ( 3 ) 329 - 338 2019.06

    ISSN  03787966

     View Summary

    © 2018, Springer Nature Switzerland AG. Background and Objective: Lithium, which is used to treat bipolar disorder, has a narrow therapeutic blood concentration range and quickly reaches clinically toxic levels. We performed a population pharmacokinetic analysis with a lithium tubular reabsorption model including urinary pH and investigated the relationship between blood lithium concentration and tremor as a side effect. Methods: Routine clinical data, including 389 serum concentrations, were collected from 214 patients orally administered an adjusted amount of lithium carbonate. Pharmacokinetics were described using a one-compartment distribution model with first-order absorption and elimination. The fractions of the MID (Li + + LiCO 3− ) and ION (2Li + + CO 32− ) forms were calculated using the Henderson–Hasselbalch equation, and the influences of these fractions on clearance (CL) were evaluated. The rate of tremor development was analyzed using a logit model. Results: Oral apparent CL (CL/F) was explained by nonrenal CL and renal CL, and renal CL was varied by the fractions of lithium forms influenced by urinary pH. The contribution of MID to CL was slightly larger than that of ION. The rate of tremor development was estimated to be more than 30% when the trough lithium concentration was greater than 1.26 mEq L −1 . Conclusion: Renal function and urinary pH are important indices in lithium treatment, so the serum concentration of lithium may be predicted based on the renal function and urinary pH.

  • Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data

    Kawamura T., Kasai H., Fermanelli V., Takahashi T., Sakata Y., Matsuoka T., Ishii M., Tanigawara Y.

    Cancer Science (Cancer Science)  109 ( 9 ) 2822 - 2829 2018.09

    ISSN  13479032

     View Summary

    © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h−1, neutrophil elimination rate constant = 0.0295 h−1, and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

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Reviews, Commentaries, etc. 【 Display / hide

  • TDM解析ソフトで算出されるベイズ推定による血中濃度予測に対する標準誤差の重要性

    榊 拓人, 笠井 英史, 伊賀 正典, 高野 温志, 町田 充, 鈴木 萌子, 佐古 兼一

    TDM研究 ((一社)日本TDM学会)  36 ( 2 ) 151 - 151 2019.05

    ISSN  0911-1026

  • 採血デザイン検討ツールの母集団薬物動態解析計画への実装 経口投与製剤を例に

    鈴木 萌子, 笠井 英史, 佐古 兼一, 浜田 幸宏, 木村 利美

    TDM研究 ((一社)日本TDM学会)  36 ( 2 ) 156 - 156 2019.05

    ISSN  0911-1026

  • 好中球減少によるクリアランス変動要因を考慮した成人がん患者におけるバンコマイシン母集団モデルのLeave-one-out法による予測性評価

    鈴木 萌子, 笠井 英史, 佐古 兼一, 浜田 幸宏, 木村 利美

    TDM研究 ((一社)日本TDM学会)  36 ( 2 ) 154 - 154 2019.05

    ISSN  0911-1026

  • 【医薬品開発におけるファーマコメトリクスの利用・適用】 ファーマコメトリクスの市販後の臨床現場への展開

    笠井 英史

    臨床医薬 ((株)臨床医薬研究協会)  34 ( 12 ) 808 - 815 2018.12

    ISSN  0910-8211

  • PDデータを用いたTDM Bayes解析ソフト開発の試み

    笠井 英史

    TDM研究 ((一社)日本TDM学会)  35 ( 2 ) 123 - 123 2018.05

    ISSN  0911-1026

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Presentations 【 Display / hide

  • 'Population Pharmacokinetic Analysis and Monte Carlo Pharmacodynamic Simulations of a New Quinolone, T-3811ME (Garenoxacin)'


    43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago) , 


    Poster presentation, American Society for Microbiology

  • モンテカルロ・シミュレーションによるレボフロキサシン臨床効果の予測


    第51回日本化学療法学会総会 (横浜) , 


    Oral presentation (general), 日本化学療法学会

  • 日本人小児感染症患者におけるメロペネムの母集団薬物動態

    Kasai Hidefumi, Yamabe Yoshikazu, Tanigawara Yuusuke, Sunagawa Keisuke



    Poster presentation

  • PK/PD

    Tanigawara Yuusuke, Kasai Hidefumi

    (財)日本科学技術連盟 医薬データの統計解析専門コース, 



  • EXCELによるバルプロ酸(バレリン)投与設計プログラムの開発

    Kasai Hidefumi,Terauchi Yoshiaki,Fujii Toshihiko,Tanigawara Yuusuke




Memberships in Academic Societies 【 Display / hide

  • 臨床薬理学会, 

  • TDM学会, 

  • American Society for Clinical Pharmacology and Therapeutics (ASCPT),