Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function

• Published in: Clinical pharmacology in drug development Vol. 11; no. 5; pp. 562 - 575
• Main Authors: Mahar, Kelly M., Shaddinger, Bonnie C., Ramanjineyulu, Bandi, Andrews, Susan, Caltabiano, Stephen, Lindsay, Alistair C., Cobitz, Alexander R.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2022; John Wiley and Sons Inc
• Subjects: anemia; Barbiturates; daprodustat; Female; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - pharmacokinetics; hepatic impairment; Humans; Liver; Liver Diseases - metabolism; Male; Metabolites; Original; Pharmacodynamics; Pharmacokinetics; Prolyl-Hydroxylase Inhibitors - adverse effects; Prolyl-Hydroxylase Inhibitors - pharmacokinetics; hepatic impairment; pharmacokinetics; daprodustat; pharmacodynamics; anemia
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.1090

Daprodustat is a hypoxia‐inducible factor‐prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. We evaluated the role of hepatic impairment on daprodustat pharmacokinetics, pharmacodynamics, and tolerability. Participants with mild (Child‐Pugh Class A, score 5‒6) and moderate (Child‐Pugh Class B, score 7‒9) hepatic impairment and matched healthy controls were administered single 6‐mg doses of daprodustat. Exposure parameters were determined for daprodustat and its six metabolites. Comparisons resulted in 1.5‐ and 2.0‐fold higher daprodustat Cmax and area under the curve (AUC) exposures in participants with mild and moderate hepatic impairment, respectively, versus controls; Cmax in mild hepatic impairment was comparable to controls. Similarly, aligned with parent drug, unbound daprodustat Cmax and AUC exposures increased 1.6‐ to 2.3‐fold in hepatic‐impaired participants versus controls, and metabolite exposures were 1.2‐ to 2.0‐fold higher in participants with hepatic impairment. Erythropoeitin (EPO) baseline‐corrected AUC exposures were between 0.3‐fold lower and 2.2‐fold higher in matched controls versus hepatic‐impaired participants. No serious or study drug‐related adverse events were reported. Daprodustat exposure was increased in participants with moderate and mild hepatic impairment compared with matched controls; however, no meaningful differences in EPO were observed and no new safety concerns were identified (ClinicalTrials.gov: NCT03223337).