Population Toxicodynamic Modeling of the Acute Kidney Injury-to-Chronic Kidney Disease Transition Following Repeated Cisplatin Administration in Rats

Cisplatin (cis-diammineplatinum (II) dichloride [CDDP]) induces acute kidney injury (AKI), and repeated dosing may lead to incomplete recovery and progression to chronic kidney disease (CKD). However, the quantitative dynamics underlying the AKI-to-CKD transition remain unclear. This study aimed to develop a mathematical model to characterize the CDDP-induced AKI-to-CKD transition during repeated administration. Rats received three cycles of CDDP at 21-d intervals under different dosing regimens, but with an identical cumulative dose (9 mg/kg). Plasma creatinine (Cr) was measured longitudinally as a marker of renal function, and values from Days 15 to 21 after each dosing cycle were used to evaluate the extent of recovery following AKI. A toxicodynamic model based on Cr mass balance was developed. The model incorporated a Hill-type function to describe CDDP-induced toxic effects and evaluated alternative structural assumptions in which toxicity progression across cycles was modeled as either additive or multiplicative. Renal function progressively decreased in a dose-dependent manner across cycles. Although Cr profiles differed among regimens during individual cycles, Cr levels converged by the end of the third cycle. The additive toxicity model, in which CDDP accumulates in a virtual kidney compartment and the toxic signal decays slowly (half-life: 79 d), best described the data (CDDP dose per body weight producing 50% inhibition: 5.11 mg/kg). To our knowledge, this study presents the first mathematical model describing the dynamics of the AKI-to-CKD transition following repeated CDDP administration. The proposed modeling approach may facilitate prediction of the AKI-to-CKD transition and support the optimization of safer CDDP treatment strategies.