Population Pharmacokinetic-Toxicodynamic Modeling and Simulation of Cisplatin-Induced Acute Renal Injury in Rats: Effect of Dosing Rate on Nephrotoxicity

作者：Fukushima Keizo; Okada Akira; Sasaki Kosho; Kishimoto Shuichi; Fukushima Shoji; Hamori Mai; Nishimura Asako; Shibata Nobuhito; Shirai Toshiharu; Terauchi Ryu; Kubo Toshikazu; Sugioka Nobuyuki^*

来源：Journal of Pharmaceutical Sciences, 2016, 105(1): 324-332.

DOI：10.1016/j.xphs.2015.10.022

• cisplatin
• nephrotoxicity
• population pharmacokinetics/
• pharmacodynamics
• pharmacokinetic/pharmacodynamic models
• toxicokinetics
• simulations
• cancer chemotherapy

Nephrotoxicity is the major dose-limiting toxicity of cisplatin (CDDP). The aim of this study was to develop a pharmacokinetic (PK)/toxicodynamic (TD) model of CDDP-induced acute renal injury in rats and to simulate nephrotoxicity at various dosing rates. CDDP was administered to rats by a 30-s bolus or a 2-h infusion (1.0, 2.5, 5.0, and 7.5 mg/kg). Unbound CDDP concentrations in plasma and urine were determined up to 2 h after administration in the PK study, and plasma creatinine (Cr) levels were monitored for up to 7 days as an index of nephrotoxicity in the TD study. The PK was linear and was fitted with a traditional 2-compartment model. The TD was nonlinear and differed between dosing rates. The creatinine concentration profiles were fitted with a signal transduction-indirect response model. Population analysis using a nonlinear mixed-effect model was adapted to the developed PK/TD model and was well-validated. Dosing simulations from the developed population PK/TD model indicated that CDDP-induced nephrotoxicity was due to not only C-max but also the time above the toxic concentration of CDDP. Prolongation of infusion time will not necessarily attenuate acute nephrotoxicity. This study demonstrated the potential utility of PK/TD modeling for preventing nephrotoxicity.

• 出版日期2016-1