Pharmakokinetic-pharmacodynamic analysis of cisplatin with hydration and mannitol diuresis

• Project/Area Number: 15K18941
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kobe Gakuin University
• Principal Investigator: Fukushima Keizo 神戸学院大学, 薬学部, 助教 (30454474)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シスプラチン / 腎障害 / 強制利尿法 / PKPD解析 / cisplatin / PKPD modeling / 薬物動態

Outline of Final Research Achievements

Forced diuresis treatment did not significantly alter the plasma cisplatin pharmacokinetics but dramatically decreased the urine concentration of unbound cisplatin and its accumulation into the kidneys in a dose-dependent manner, and correspondingly, nephrotoxicity was dose-dependently attenuated by forced diuresis. The pharmacokinetic-pharmacodynamic analysis suggested that the urine cisplatin concentration has a comparable impact on the cisplatin-induced nephrotoxicity to that in plasma, probably owing to the reabsorption of cisplatin from urine, which can be attenuated by forced diuresis. These results indicated that the nephroprotective effect of forced diuresis is a pharmacokinetic-based drug-drug interaction possibly due to the inhibition of cisplatin reabsorption from urine. Monitoring of urine cisplatin concentration may lead to the optimization of a forced diuresis protocol with mannitol.

Research Products

• [Journal Article] Pharmacokinetic-Pharmacodynamic Analysis of Cisplatin with Hydration and Mannitol Diuresis: The Contribution of Urine Cisplatin Concentration to Nephrotoxicity. (2018)
  • Author(s): Fukushima K, Okada A, Oe H, Hirasaki M, Hamori M, Nishimura A, Shibata N, Sugioka N.
  • Journal Title: Eur J Drug Metab Pharmacokinet Volume: 43 Issue: 2 Pages: 193-203
  • DOI: 10.1007/s13318-017-0436-8
  • Peer Reviewed
• [Journal Article] Population Pharmacokinetic-Toxicodynamic Modeling and Simulation of Cisplatin-Induced Acute Renal Injury in Rats: Effect of Dosing Rate on Nephrotoxicity. (2016)
  • Author(s): Fukushima K, Okada A, Sasaki K, Kishimoto S, Fukushima S, Hamori M, Nishimura A, Shibata N, Shirai T, Terauchi R, Kubo T, Sugioka N.
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 105 Issue: 1 Pages: 324-332
  • DOI: 10.1016/j.xphs.2015.10.022
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 強制利尿法の用量が抗がん剤cisplatinの薬物動態および腎障害軽減作用に及ぼす影響. (2017)
  • Author(s): 岡田 章, 大江 裕之, 平崎 実花, 中西 真那, 藤田 まい, 福島 恵造, 杉岡 信幸.
  • Organizer: 第137年会 日本薬学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2017-03-24