In Vitro and Clinical Pharmacokinetic Studies of the Effects of Iron-containing Agents on Vadadustat, an Oral Hypoxia-inducible Factor–Prolyl Hydroxylase Inhibitor
| Autor: | Yoshimasa Kokado, Kouji Kawai, Shuji Kinoshita, Takehiro Nanjo, Kazuoki Kondo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Anemia Iron Sodium Glycine Cmax chemistry.chemical_element Pharmacology Ferrous chemistry.chemical_compound Pharmacokinetics Humans Medicine Pharmacology (medical) Chelation Hypoxia Picolinic Acids Ferrous citrate business.industry Prolyl-Hydroxylase Inhibitors medicine.disease chemistry Ferric business medicine.drug |
| Zdroj: | Clinical Therapeutics. 43:1408-1418.e5 |
| ISSN: | 0149-2918 |
| DOI: | 10.1016/j.clinthera.2021.06.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect