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

被引：14

作者：

Fukushima, Keizo ^{[1
]}

Okada, Akira ^{[1
]}

Sasaki, Kosho ^{[1
]}

Kishimoto, Shuichi ^{[2
]}

Fukushima, Shoji ^{[2
]}

Hamori, Mai ^{[3
]}

Nishimura, Asako ^{[3
]}

Shibata, Nobuhito ^{[3
]}

Shirai, Toshiharu ^{[4
]}

Terauchi, Ryu ^{[4
]}

Kubo, Toshikazu ^{[4
]}

Sugioka, Nobuyuki ^{[1
]}

机构：

[1] Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Clin Pharmacokinet, Chuo Ku, Kobe, Hyogo 6508586, Japan

[2] Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Pharmaceut, Chuo Ku, Kobe, Hyogo 6508586, Japan

[3] Doshisha Womens Coll Liberal Arts, Fac Pharmaceut Sci, Dept Biopharmaceut, Kyoto 6100395, Japan

[4] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Orthopaed, Kyoto 6028566, Japan

来源：

JOURNAL OF PHARMACEUTICAL SCIENCES | 2016年 / 105卷 / 01期

基金：

日本学术振兴会;

关键词：

cisplatin; nephrotoxicity; population pharmacokinetics/; pharmacodynamics; pharmacokinetic/pharmacodynamic models; toxicokinetics; simulations; cancer chemotherapy; ADVANCED SOLID TUMORS; UNCHANGED CISPLATIN; CANCER-PATIENTS; PHASE-I; PLASMA; CAPECITABINE; DISPOSITION; ACTIVATION; APOPTOSIS; TOXICITY;

D O I：

10.1016/j.xphs.2015.10.022

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

引用

页码：324 / 332

页数：9

共 35 条

[1] Apoptosis by cisplatin requires p53 mediated p38α MAPK activation through ROS generation [J].