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

Abstract

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).

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study

“…Plasma daprodustat data were collected as previously described 17,19 and calculated via standard noncompartmental analysis with WinNonlin 6.3 or higher (Certara, Princeton, NJ). All calculations were based on actual sampling times.…”

“…Clinical data have shown that daprodustat administered orally is rapidly absorbed, with time to maximum concentration (t max ) of 1–4 hours, and exhibits dose‐proportional increases in exposure 15–17 . The pharmacokinetic (PK) profile of daprodustat is similar in the healthy adult and CKD populations as the maximum observed drug concentration (C max ), area under concentration‐time curve (AUC), and t max have been shown to be comparable in both groups 18 .…”

Daprodustat

“…16 Daprodustat C max and AUC were increased 2-fold in participants with moderate (Child-Pugh class B) hepatic impairment versus healthy controls; in participants with mild hepatic impairment, C max was comparable with controls and AUC was increased 1.5-fold. 1,17…”