In Vitro and Clinical Pharmacokinetic Studies of the Effects of Iron-containing Agents on Vadadustat, an Oral Hypoxia-inducible Factor-Prolyl Hydroxylase Inhibitor

Abstract

Purpose: Vadadustat is an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in chronic kidney disease. This study investigated drug-drug interactions between vadadustat and oral iron supplements or iron-containing phosphate binders commonly used in Japanese clinical practice by conducting in vitro mechanistic and clinical pharmacokinetic studies.

Methods: In the in vitro assessment, chelate formation of vadadustat with iron-containing agents was investigated in water and in a fed-state simulated intestinal fluid. Chelate formation was assessed by observation of a chelate-specific color, and the concentration of vadadustat was determined. In the single-dose, open-label, randomized, crossover clinical study, healthy male participants received 150 mg of vadadustat with or without oral iron-containing agents. Pharmacokinetic data were collected for up to 24 hours after vadadustat administration. Participants were monitored for adverse events during the study.

Findings: Vadadustat formed a chelate precipitate with ferrous sulfate and ferric nitrate, as shown by development of a specific bright orange color in water. The proportions of vadadustat dissolved in the supernatant were 2% and 18%, respectively. Vadadustat did not form a chelate precipitate in a fed-state simulated intestinal fluid in the presence of sodium ferrous citrate, ferric citrate hydrate, or sucroferric oxyhydroxide; the proportion of vadadustat in supernatant ranged from 63% to 89%. In the clinical pharmacokinetic study, coadministration of vadadustat with sodium ferrous citrate, ferric citrate hydrate, sucroferric oxyhydroxide, or ferrous sulfate decreased the AUC0-∞ by 54.0% to 89.7% and Cmax by 42.1% to 91.9%. No serious adverse events were reported.

Implications: Chelate formation of vadadustat with iron-containing agents was confirmed by in vitro analysis and depended on the type of iron-containing agent. The AUC0-∞ and Cmax of vadadustat decreased when coadministered with oral iron-containing agents. Our data suggest that the decreases in AUC0-∞ and Cmax are a result of chelation in the gastrointestinal tract; therefore, coadministration of iron-containing agents with vadadustat should use a dosing interval. ClinicalTrials.gov Identifier: NCT03645863.

Keywords: anemia in chronic kidney disease; chelate formation; hypoxia-inducible factor–prolyl hydroxylase inhibitor; iron-containing phosphate binder; oral iron supplements; vadadustat.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.