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

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 Cmax 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.

Journal of pharmaceutical sciences. 2015 Dec 22 [Epub]

Keizo Fukushima, Akira Okada, Kosho Sasaki, Shuichi Kishimoto, Shoji Fukushima, Mai Hamori, Asako Nishimura, Nobuhito Shibata, Toshiharu Shirai, Ryu Terauchi, Toshikazu Kubo, Nobuyuki Sugioka

Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. , Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. , Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. , Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. , Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. , Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan. , Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan. , Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan. , Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. , Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. , Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. , Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan.  

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