Influence of acute and chronic kidney failure in rats on the disposition and pharmacokinetics of ZYAN1, a novel prolyl hydroxylase inhibitor, for the treatment of chronic kidney disease-induced anemia

Abstract

1. ZYAN1 is a prolyl hydroxylase inhibitor in clinical development for treatment of anemia associated with chronic kidney disease (CKD). We evaluated the effect of acute and chronic kidney impairment on the pharmacokinetics of ZYAN1 in rat models.

2. Cisplatin (2.5, 5 and 7.5 mg/kg) was used to induce acute kidney injury (AKI), and five-sixth and total nephrectomy was used to induce chronic kidney injury (CKI) in male Wistar rats. All groups received a single 15 mg/kg oral dose of ZYAN1. Blood/urine samples were analyzed for ZYAN1 to assess peak concentration (C_max), area under the concentration–time curve (AUC_inf), total body clearance (CL/F) and elimination half-life (T_1/2).

3. C_max and AUC_inf were not significantly different in the various AKI groups or in five-sixth nephrectomized rats, as compared to control rats. Recovery of ZYAN1 in urine was reduced; the impact on the CL/F was minimal. There was a 2-fold increase in AUC_inf with reduction in CL/F in total nephrectomized rats. T_1/2 was longer for ZYAN1 in the severe AKI/five-sixth nephrectomy rats and total nephrectomy rats as compared to control rats.

4. Based on the rodent data it may be inferred that PK of ZYAN1 in CKD patients may be minimally affected.

Keywords:

• Acute kidney injury
• anemia
• erythropoietin
• nephrectomy
• pharmacokinetics
• ZYAN1

Declaration of interest

All the authors are employees of Cadila Healthcare Limited. The authors have no conflicts of interest to declare on the content of this research work (ZRC communication no.: 497). There was no external funding received for this work.