Kidney Week

Abstract: TH-PO369

Effect of Moderate Hepatic Impairment on Pharmacokinetics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI)

Session Information

• Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Chavan, Ajit B., Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Ajit B. Chavan,

• Paulson, Susan K., Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Susan K. Paulson,

• Burke, Leontia, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Leontia Burke,

• Sawant, Rishikesh, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Rishikesh Sawant,

• Schwartz, Brian, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Brian Schwartz,

• deGoma, Emil, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States

Emil deGoma,

Background

Vadadustat is an oral HIF-PHI in development for the treatment of anemia due to chronic kidney disease. Vadadustat is primarily metabolized to O-glucuronide by UPD-glucuronosyltransferases (UGTs). The predominant UGT involved in the metabolism of vadadustat is UGT1A9, which is expressed in the liver and kidney. Therefore, the role of hepatic impairment in vadadustat clearance was evaluated.

Methods

This phase 1, open-label, parallel-group, single-dose study evaluated pharmacokinetics (PK) of 450 mg vadadustat in adults (18-70 y) with moderate hepatic impairment (Child-Pugh Class B) versus those with normal hepatic function. Blood samples were collected pre-dose and up to 72 h post-dose. Primary endpoints were area under the curve from dosing to last concentrations (AUC_last) and to infinity (AUC_inf) as well as maximum concentration (C_max); additional PK parameters included time to C_max (T_max) and half-life (t_1/2). Safety and tolerability were assessed throughout the study.

Results

All 16 enrolled participants completed the study (hepatic impairment, n=8; normal, n=8). Demographics were similar between groups (overall: 100% white, 62.5% female, mean age 59.2 y). Vadadustat plasma exposure (AUC) was slightly higher in the hepatic impairment group, whereas C_max was generally similar between groups (Table). Point estimates of the hepatic impairment:normal geometric mean ratios (90% CI) for AUC_last, AUC_inf, and C_max were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 h in the normal group and 7.8 h in the hepatic impairment group. Treatment-emergent adverse events (TEAEs) were reported by 1 participant in the hepatic impairment group and 2 in the normal group. Most TEAEs (86% [6/7]) were mild in severity; none were severe.

Conclusion

In this study, moderate hepatic impairment did not significantly impact vadadustat systemic exposure. A single dose of 450 mg vadadustat was generally well tolerated by participants with both normal and moderately impaired hepatic function.

Values=arithmetic mean (% coefficient of variation) except Tmax, shown as median (range)

Funding

• Commercial Support –