title: 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 (Cmax), area under the concentration-time curve (AUCinf), total body clearance (CL/F) and elimination half-life (T1/2). 3. Cmaxand AUCinfwere 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 AUCinfwith reduction in CL/F in total nephrectomized rats. T1/2was 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.
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics.
authors.forename: Harilal
authors.initials: H
authors.lastname: Patel
authors.affiliation: b Department of Pharmacology and Toxicology , and.
authors.forename: Amit Arvind
authors.initials: AA
authors.lastname: Joharapurkar
authors.affiliation: c Department of Medicinal chemistry , Zydus Research Centre, Cadila Healthcare Limited , Ahmedabad , India.
authors.forename: Vrajesh Bhaskarbhai
authors.initials: VB
authors.lastname: Pandya
authors.affiliation: b Department of Pharmacology and Toxicology , and.
authors.forename: Vishal Jagjivanbhai
authors.initials: VJ
authors.lastname: Patel
authors.affiliation: b Department of Pharmacology and Toxicology , and.
authors.forename: Samadhan Govind
authors.initials: SG
authors.lastname: Kshirsagar
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics.
authors.forename: Prakash
authors.initials: P
authors.lastname: Patel
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics.
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Gevriya
authors.affiliation: b Department of Pharmacology and Toxicology , and.
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics.
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
authors.affiliation: a Department of Drug Metabolism and Pharmacokinetics.|b Department of Pharmacology and Toxicology , and.|c Department of Medicinal chemistry , Zydus Research Centre, Cadila Healthcare Limited , Ahmedabad , India.
authors.forename: Pankaj Ramanbhai
authors.initials: PR
authors.lastname: Patel
authors.affiliation: c Department of Medicinal chemistry , Zydus Research Centre, Cadila Healthcare Limited , Ahmedabad , India.
authors.forename: Ranjit C
authors.initials: RC
authors.lastname: Desai
mesh_terms: D000740:Anemia / Q000150:complications / Q000188:drug therapy; D000818:Animals; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D015363:Quinolones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015363:Quinolones; C000623340:desidustat
keywords: Acute kidney injury; ZYAN1; anemia; erythropoietin; nephrectomy; pharmacokinetics