[Studies of the Various Chronic Kidney Failure Rat Models and Hemodialysis Mini-pig Model for the Evaluation of Anti-hyperphosphatemia Drugs].

ABSTRACT

Animal models of chronic kidney failure (CKF) have been developed for the pharmacodynamic evaluation of various phosphate binders that are used clinically to treat hyperphosphatemia in patients with chronic kidney disease. However, these models represent different disease states and severities, depending on the experimental conditions and are not clearly defined for pharmacological evaluation. In addition, experimental models have not yet been established for artificial dialysis. The purpose of this study was to confirm the utility of the various rat models of CKF and the mini-pig model of hemodialysis as models of hyperphosphatemia for pharmacodynamic evaluation. Various rat models of pre-dialysis CKF (oral adenine dosing, 5/6 resection, and ligation nephrectomy model) were evaluated through determinations of serum and urinary parameters (osmolality, creatinine, and phosphorus), pathological observations of kidney, and the phosphorus-absorbing properties of lanthanum carbonate (La) formulations. The rat and mini-pig models were compared based on each evaluation index. In the oral adenine dosing model, serum phosphorus increased markedly and the area under the serum phosphorus concentration-time curve (phosphorus AUC) decreased in a dose-dependent manner with the administration of La formulations. In contrast, a significant decrease in serum phosphorus AUC, a prolongation of the dialysis interval, and an improvement in dialysis efficiency were observed after administration of La formulations to the mini-pig hemodialysis model. Furthermore, the results of bioequivalence studies between two La formulations (Fosrenol and SW670, a generic formulation) suggested that the rat and mini-pig models are useful and precise as pre-dialysis and dialysis models, respectively.