Population pharmacokinetic analysis of anti-infective drugs considering clearance with/without continuous renal replacement therapy in intensive care unit patients

• Project/Area Number: 20K16048
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Oita University
• Principal Investigator: Ryota Tanaka 大分大学, 医学部, 准教授 (30781736)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 母集団薬物動態モデル / 抗感染症薬 / 集中治療 / 集中治療領域 / 持続的腎代替療法 / テジゾリド / テイコプラニン / カルバペネム / 抗MRSA薬 / キノロン / ドリペネム

Outline of Research at the Start

集中治療を必要とする重症感染者では多岐の要因から体内動態が変動するため、一般病床者とは異なった動態モデルを基にした投与設計が望ましい。過去にICU入室中の重症感染症患者や持続的腎代替療法（CRRT）施行患者を対象とした抗感染症薬の母集団薬物動態（PPK）解析に関する報告は存在する。しかし、同モデルにおいてICU入室の全患者を対象にCRRTによるクリアランスの有無を考慮して検討した報告はない。このような背景のもと、本研究では異なる薬物動態学的特徴を示すドリペネム、リネゾリドおよびテジゾリドに焦点を当て、CRRTによるクリアランスの有無を考慮したPPKモデルを構築することを目的とした。

Outline of Final Research Achievements

The present research aimed to develop population pharmacokinetic (PPK) models considering clearance with/without continuous renal replacement therapy (CRRT) of anti-MRSA agents and carbapenems frequently used for empirical treatment in patients with severe infection admitted to the intensive care unit (ICU). At first, we successfully established the high-throughput simultaneous quantification method for these anti-infective agents and high sensitive quantification method for total and free concentrations. Next, we attempted a PPK analysis of doripenem with ADVAN6 of NONMEM for ICU patients. The model fit was refined by incorporating the clearance with CRRT into an elimination pathway, succeeding in building a doripenem PPK model considering clearance with/without CRRT.

Academic Significance and Societal Importance of the Research Achievements

本研究結果より、ドリペネムの全身クリアランスへのCRRTの寄与は約40%であることが判明した。また、構築したモデルを用いて、EUCASTの緑膿菌に対するブレイクポイントを基準に、腎機能とCRRTの有無で場合分けした場合のモンテカルロシミュレーションを実施した結果、腎機能だけでなくCRRTの有無で至適投与量が異なることが明らかとなった。ICU患者におけるドリペネムの投与設計を実施する際に本モデルを用いることで、CRRTの有無で使用するPPKモデルを変更することなく単一のモデルで評価可能になり、ICU入室中の重症感染症患者に初期経験的治療を行う際の最適な投与設計に貢献できると期待される。

Research Products

• [Journal Article] Positive correlation between organic anion transporter 1B function indicated by plasma concentration of coproporphyrin-I and blood concentration of cyclosporin A in real-world patients. (2023)
  • Author(s): Watanabe T, Tanaka R, Suzuki Y, Sato H, Negami J, Yoshijima C, Oda A, Ono H, Tatsuta R, Ohno K, Itoh H.
  • Journal Title: Br J Clin Pharmacol Volume: 89(5) Issue: 5 Pages: 1672-1681
  • DOI: 10.1111/bcp.15640
  • Peer Reviewed
• [Journal Article] UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy (2023)
  • Author(s): Kai Makoto、Tanaka Ryota、Suzuki Yosuke、Goto Koji、Ohchi Yoshifumi、Yasuda Norihisa、Tatsuta Ryosuke、Kitano Takaaki、Itoh Hiroki
  • Journal Title: Journal of Clinical Laboratory Analysis Volume: 37 Issue: 1
  • DOI: 10.1002/jcla.24815
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Inflammation on Intra-individual Variation in Trough Voriconazole Concentration in Patients with Hematological Malignancies (2022)
  • Author(s): Maeda Y, Tanaka R, Tatsuta R, Takano K, Hashimoto T, Ogata M, Hiramatsu K, Itoh H.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 8 Pages: 1084-1090
  • DOI: 10.1248/bpb.b22-00097
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-08-01
  • Peer Reviewed / Open Access
• [Journal Article] High-throughput simultaneous quantification of five azole anti-fungal agents and one active metabolite in human plasma using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (2022)
  • Author(s): Tanaka Ryota、Shiraiwa Ken、Takano Kuniko、Ogata Masao、Honda Shuhei、Yoshida Natsumi、Okuhiro Kazuki、Yoshida Masaki、Narahara Kumiko、Kai Makoto、Tatsuta Ryosuke、Itoh Hiroki
  • Journal Title: Clinical Biochemistry Volume: 99 Pages: 87-96
  • DOI: 10.1016/j.clinbiochem.2021.10.010
  • Peer Reviewed
• [Journal Article] High-Sensitivity and High-Throughput Quantification of Everolimus in Human Whole Blood Using Ultrahigh-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry. (2022)
  • Author(s): Miyagi C, Tanaka R, Hirata K, Watanabe T, Tatsuta R, Miyamura S, Itoh H.
  • Journal Title: Ther Drug Monit Volume: 44(5) Issue: 5 Pages: 633-640
  • DOI: 10.1097/ftd.0000000000000985
  • Peer Reviewed
• [Journal Article] Sustained suppression of enterohepatic circulation of mycophenolic acid by antimicrobial-associated diarrhea in a kidney transplant recipient with Crohn's disease: A case report. (2022)
  • Author(s): Tanaka R, Matsumoto A, Tatsuta R, Ando T, Shin T, Mimata H, Itoh H.
  • Journal Title: Clin Case Rep Volume: 10(6) Issue: 6
  • DOI: 10.1002/ccr3.5914
  • Peer Reviewed / Open Access
• [Journal Article] A validated UHPLC-MS/MS method for quantification of total and free tedizolid concentrations in human plasma (2022)
  • Author(s): Tanaka Ryota、Kai Makoto、Shinohara Saori、Tatsuta Ryosuke、Itoh Hiroki
  • Journal Title: Journal of Pharmaceutical and Biomedical Analysis Volume: 219 Pages: 114929-114929
  • DOI: 10.1016/j.jpba.2022.114929
  • Peer Reviewed
• [Journal Article] Association of Vancomycin Trough Concentration and Clearance With Febrile Neutropenia in Pediatric Patients. (2022)
  • Author(s): Amano E, Tanaka R, Ono H, Tatsuta R, Hashimoto T, Hiramatsu K, Itoh H.
  • Journal Title: Ther Drug Monit Volume: 44(4) Issue: 4 Pages: 543-551
  • DOI: 10.1097/ftd.0000000000000978
  • Peer Reviewed
• [Journal Article] Exacerbation of cancer pain after administering immune checkpoint inhibitor in a patient taking opioids: A case report. (2022)
  • Author(s): Sumimoto T, Tanaka R, Shiraiwa K, Tatsuta R, Itoh H.
  • Journal Title: J Clin Pharm Ther Volume: 47(4) Issue: 4 Pages: 552-555
  • DOI: 10.1111/jcpt.13541
  • Peer Reviewed
• [Journal Article] Pharmacokinetic and Adsorptive Analyses of Administration of Oral Voriconazole Suspension <i>via</i> Enteral Feeding Tube in Intensive Care Unit Patients (2021)
  • Author(s): Tanaka R, Eto D, Goto K, Ohchi Y, Yasuda N, Suzuki Y, Tatsuta R, Kitano T, Itoh H.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 44 Issue: 5 Pages: 737-741
  • DOI: 10.1248/bpb.b20-00796
  • NAID: 130008033238
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2021-05-01
  • Peer Reviewed
• [Journal Article] Simultaneous quantification of plasma levels of 12 antimicrobial agents including carbapenem, anti-methicillin-resistant Staphylococcus aureus agent, quinolone and azole used in intensive care unit using UHPLC-MS/MS method (2021)
  • Author(s): Kai Makoto、Tanaka Ryota、Suzuki Yosuke、Goto Koji、Ohchi Yoshifumi、Yasuda Norihisa、Tatsuta Ryosuke、Kitano Takaaki、Itoh Hiroki
  • Journal Title: Clinical Biochemistry Volume: 90 Pages: 40-49
  • DOI: 10.1016/j.clinbiochem.2021.01.012
  • Peer Reviewed
• [Journal Article] Significant elevation of free itraconazole concentration at onset of adverse effects: A case report. (2021)
  • Author(s): Tanaka R, Suzuki Y, Matsumoto H, Yamasue M, Umeki K, Hashinaga K, Tatsuta R, Hiramatsu K, Kamei K, Kadota JI, Itoh H.
  • Journal Title: Clin Case Rep Volume: 9(3) Issue: 3 Pages: 1187-1192
  • DOI: 10.1002/ccr3.3726
  • Peer Reviewed / Open Access
• [Journal Article] Sensitive, wide-range and high-throughput quantification of cyclosporine in whole blood using ultra-performance liquid chromatography coupled to tandem mass spectrometry and comparison with an antibody-conjugated magnetic immunoassay. (2021)
  • Author(s): Watanabe T, Tanaka R, Ono H, Suzuki Y, Tatsuta R, Itoh H.
  • Journal Title: Biomed Chromatogr Volume: 35(8) Issue: 8
  • DOI: 10.1002/bmc.5128
  • Peer Reviewed
• [Journal Article] Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end-stage renal disease. (2021)
  • Author(s): Tanaka R, Suzuki Y, Watanabe H, Fujioka T, Hirata K, Shin T, Ando T, Ono H, Tatsuta R, Mimata H, Maruyama T, Itoh H.
  • Journal Title: Clin Transl Sci Volume: 14(5) Issue: 5 Pages: 2034-2042
  • DOI: 10.1111/cts.13065
  • Peer Reviewed / Open Access
• [Journal Article] Factors Influencing Plasma Coproporphyrin-I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis (2021)
  • Author(s): Ono H, Tanaka R, Suzuki Y, Oda A, Ozaki T, Tatsuta R, Maeshima K, Ishii K, Ohno K, Shibata H, Itoh H.
  • Journal Title: Clin Pharmacol Ther Volume: 110 Issue: 4 Pages: 1096-1105
  • DOI: 10.1002/cpt.2375
  • Peer Reviewed
• [Journal Article] Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control. (2021)
  • Author(s): Iwao M, Tanaka R, Suzuki Y, Nakata T, Aoki K, Fukuda A, Fukunaga N, Tatsuta R, Ohno K, Shibata H, Itoh H.
  • Journal Title: Sci Rep Volume: 11(1) Issue: 1 Pages: 21931-21931
  • DOI: 10.1038/s41598-021-01403-2
  • Peer Reviewed / Open Access
• [Journal Article] A case of improvement of clozapine-induced low leukocyte counts by adenine, cepharanthin and ninjin-yoei-to in a patient with treatment-resistant schizophrenia. (2021)
  • Author(s): Kamei S, Tanaka R, Hirakawa H, Iwao M, Kawanaka R, Tatsuta R, Terao T, Itoh H.
  • Journal Title: J Pharm Health Care Sci Volume: 7(1) Issue: 1 Pages: 45-45
  • DOI: 10.1186/s40780-021-00227-6
  • Peer Reviewed / Open Access
• [Journal Article] High-throughput and wide-range simultaneous determination of linezolid, daptomycin and tedizolid in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (2021)
  • Author(s): Tanaka Ryota、Kai Makoto、Goto Koji、Ohchi Yoshifumi、Yasuda Norihisa、Tatsuta Ryosuke、Kitano Takaaki、Itoh Hiroki
  • Journal Title: Journal of Pharmaceutical and Biomedical Analysis Volume: 194 Pages: 113764-113764
  • DOI: 10.1016/j.jpba.2020.113764
  • Peer Reviewed
• [Journal Article] Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit (2020)
  • Author(s): Nonoshita Ko、Suzuki Yosuke、Tanaka Ryota、Kaneko Tetsuya、Ohchi Yoshifumi、Sato Yuhki、Yasuda Norihisa、Goto Koji、Kitano Takaaki、Itoh Hiroki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 22148-22148
  • DOI: 10.1038/s41598-020-79076-6
  • Peer Reviewed / Open Access
• [Journal Article] A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis (2020)
  • Author(s): Tanaka Ryota、Fujioka Takashi、Suzuki Yosuke、Iwao Motoshi、Itoh Hiroki
  • Journal Title: Chemotherapy Volume: 65 Issue: 3-4 Pages: 59-64
  • DOI: 10.1159/000509970
  • Peer Reviewed
• [Journal Article] A retrospective test for a possible relationship between linezolid‐induced thrombocytopenia and hyponatraemia (2020)
  • Author(s): Tanaka Ryota、Suzuki Yosuke、Morinaga Yuko、Iwao Motoshi、Takumi Yukie、Hashinaga Kazuhiko、Tatsuta Ryosuke、Hiramatsu Kazufumi、Kadota Jun‐ichi、Itoh Hiroki
  • Journal Title: Journal of Clinical Pharmacy and Therapeutics Volume: 46 Issue: 2 Pages: 343-351
  • DOI: 10.1111/jcpt.13287
  • Peer Reviewed
• [Presentation] イトラコナゾールの未変化体および活性代謝物のin vivoにおける遊離型分率および遊離型濃度の比較検討 (2023)
  • Author(s): 岩男元志、田中遼大、鈴木陽介、平松和史、伊東弘樹
  • Organizer: 第71回化学療法学会学術集会
• [Presentation] LC/MS/MS分離分析微量測定法への期待 (2022)
  • Author(s): 田中遼大
  • Organizer: 第38回日本TDM学会・学術大会
  • Invited
• [Presentation] UHPLC-MS/MSを用いた総・遊離型テジゾリド濃度の高感度な同時定量法の確立 (2022)
  • Author(s): 甲斐 真己都、田中 遼大、篠原 沙織、龍田 涼佑、伊東 弘樹
  • Organizer: 第38回日本TDM学会・学術大会
• [Presentation] テイコプラニン使用時の腎障害発現に対するタゾバクタム/ピペラシリン併用の影響評価 (2022)
  • Author(s): 森永 裕子、田中 遼大、平松 和史、伊東 弘樹
  • Organizer: 第70回日本化学療法学会総会
• [Presentation] 薬物動態/薬力学解析による持続的腎代替療法施行下におけるシプロフロキサシン投与法の妥当性評価 (2022)
  • Author(s): 甲斐 真己都，田中 遼大，後藤 孝治，大地 嘉史，安田 則久，鈴木 陽介，龍田 涼佑，北野 敬明，伊東 弘樹
  • Organizer: 日本集中治療医学会第6回九州支部学術集会
• [Presentation] 新生児におけるゲンタマイシンの血中濃度に影響を及ぼす因子の探索 (2022)
  • Author(s): 津下遥香、田中遼大、龍田涼佑、衛藤恵理子、井上真紀、関口和人、前田知己、井原健二、伊東弘樹
  • Organizer: 第28回大分小児保健学会
• [Presentation] 特殊病態下の薬物動態情報を基盤とした個別化医療への展開 (2022)
  • Author(s): 田中遼大
  • Organizer: 第32回日本医療薬学会年会
  • Invited
• [Presentation] 発熱性好中球減少症や過大腎クリアランスがテイコプラニンの血中濃度および薬物動態に与える影響評価 (2022)
  • Author(s): 近藤 望、田中 遼大、龍田 涼佑、伊東 弘樹
  • Organizer: 第32回日本医療薬学会年会
• [Presentation] 新生児期の腎機能関連因子の変化量に着目したゲンタマイシン血中濃度に影響を及ぼす因子の探索 (2022)
  • Author(s): 津下遥香、田中遼大、龍田涼佑、衛藤恵理子、井上真紀、関口和人、前田知己、井原健二、伊東弘樹
  • Organizer: 第16回日本腎臓病薬物療法学会学術集会・総会
• [Presentation] 年齢区分に着目した小児バンコマイシン血中濃度に対する発熱性好中球減少症の影響 (2022)
  • Author(s): 小野寛之、田中遼大、海士野恵理乃、龍田涼佑、橋本武博、平松和史、伊東弘樹
  • Organizer: 第49回日本小児臨床薬理学会学術集会
• [Presentation] 発熱性好中球減少症の有無がバンコマイシンの小児薬物動態に与える影響 (2021)
  • Author(s): 田中遼大，岩男元志，平松和史，伊東弘樹
  • Organizer: 第68回日本化学療法学会総会
• [Presentation] in vivoにおける各種hemofilterに対するドリペネムの吸着性評価 (2021)
  • Author(s): 甲斐真己都，田中遼大，後藤孝治，大地嘉史，安田則久，鈴木陽介，龍田 涼佑，北野 敬明，伊東 弘樹
  • Organizer: 日本集中治療医学会 第5回九州支部学術集会
• [Presentation] 血液悪性疾患患者を対象としたボリコナゾール血中濃度の個体内変動に影響を及ぼす因子の探索 (2021)
  • Author(s): 前田悠，田中遼大，龍田涼佑，伊東弘樹
  • Organizer: 第31回日本医療薬学会年会
• [Presentation] In vivo Evaluation of Adsorption of Doripenem and Ciplofloxacin to Different Hemofilters. (2021)
  • Author(s): Makoto Kai, Ryota Tanaka, Koji Goto, Yoshifumi Ohchi, Norihisa Yasuda, Yosuke Suzuki, Ryosuke Tatsuta, Takaaki Kitano, Hiroki Itoh.
  • Organizer: 第15回次世代を担う若手のための医療薬科学シンポジウム
• [Presentation] 発熱性好中球減少症の有無がバンコマイシンの小児薬物動態に与える影響～年代別の検討～ (2021)
  • Author(s): 田中遼大，岩男元志，平松和史，伊東弘樹
  • Organizer: 第69回日本化学療法学会西日本支部総会
• [Presentation] UHPLC-MS/MSを用いたハイスループットかつ迅速な3種の新規抗MRSA薬同時定量法の開発と集中治療患者への臨床応用 (2021)
  • Author(s): 田中遼大，甲斐真己都，後藤孝治，大地嘉史，安田則久，龍田涼佑，北野敬明，伊東弘樹
  • Organizer: 第38回日本薬学会九州山口支部大会
• [Presentation] ハイスループットかつ高感度な6種のアゾール系抗真菌薬および代謝物の同時定量法の開発と臨床応用 (2021)
  • Author(s): 田中遼大，白岩健，高野久仁子，緒方正男，甲斐真己都，龍田涼佑，伊東弘樹
  • Organizer: 第42回日本臨床薬理学会学術総会
• [Presentation] Study on free fraction of antimicrobial agents with high protein binding rates (2021)
  • Author(s): Ryota Tanaka
  • Organizer: 第37回日本TDM学会・学術大会
  • Invited
• [Presentation] 血中濃度の予測が外れた！何を疑う？どう対応する？ (2021)
  • Author(s): 田中遼大
  • Organizer: 医療薬学フォーラム2021
  • Invited
• [Presentation] UHPLC-MS/MSを用いた7種の広域抗菌薬の濾液中濃度同時測定系の確立 (2021)
  • Author(s): 甲斐真己都、田中遼大、鈴木陽介、山村亮太、後藤孝治、大地嘉史、安田則久、龍田涼佑、北野敬明、伊東弘樹
  • Organizer: 日本薬学会第141年会