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Clinical Trial
. 2025 Aug 11;26(1):453.
doi: 10.1186/s12882-025-04367-x.

A randomized trial to evaluate the pharmacokinetics, pharmacodynamics, and safety of vadadustat in patients with anemia associated with chronic kidney disease receiving hemodialysis

Pamela Navarro-Gonzales  1 , Ajit Chavan  1 , Don Wang  1 , Steven K Burke  1 , Kevin Dykstra  2
Affiliations
Clinical Trial

A randomized trial to evaluate the pharmacokinetics, pharmacodynamics, and safety of vadadustat in patients with anemia associated with chronic kidney disease receiving hemodialysis

Pamela Navarro-Gonzales et al. BMC Nephrol. .

Abstract

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia in dialysis-dependent chronic kidney disease (CKD) with a starting dose of 300 mg once daily (dose adjustments up to 600 mg). A recent phase 1b study evaluated the pharmacokinetics, pharmacodynamics, and safety of higher vadadustat doses (500-900 mg) in healthy volunteers. Here we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher doses of vadadustat in patients with CKD receiving dialysis.

Methods: This phase 1b, randomized, open-label study evaluated the pharmacokinetics and pharmacodynamics of vadadustat (600, 750, or 900 mg) in patients with CKD-related anemia receiving hemodialysis over a 10-day treatment period. Forty-six eligible patients were randomized to vadadustat 600, 750, or 900 mg daily or an intravenous erythropoiesis-stimulating agent. For vadadustat groups, blood samples for PK and PD analyses were collected on Day 1 and Day 8. PK analyses included area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration and to infinity, and to maximum plasma concentration (Cmax). PD analyses measured serum erythropoietin (EPO), hemoglobin, and red blood cells (RBCs). Safety assessments included adverse events in the safety population (patients who received ≥ 1 dose of study drug). Patients underwent a 30-day safety follow-up period after the last dose of study drug.

Results: In the vadadustat groups, a dose-dependent increase in plasma exposure of vadadustat (Cmax and AUC) with modest accumulation was observed on Day 1 and Day 8. Vadadustat increased plasma EPO concentrations, with a variable EPO response observed in each group. Relative to baseline, mean hemoglobin and RBC levels remained unchanged, with no significant changes observed in any treatment group. Vadadustat was welltolerated.

Conclusions: The current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies.

Trial registration: ClinicalTrials.gov ID NCT03992066; https://clinicaltrials.gov/study/NCT03992066 ; Retrospectively registered on June 18, 2019. Accessed January 13, 2025.

Keywords: HIF-PHI; Pharmacodynamics; Pharmacokinetics; Phase 1; Safety; Vadadustat.

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Conflict of interest statement

Declarations. Ethics approval: The study was conducted in accordance with the protocol, ethical principles of the Declaration of Helsinki, Good Clinical Practice, and International Conference on Harmonisation guidelines, as well as all other applicable regulations. Prior to study implementation, investigators obtained approval from a central institutional review board (IRB; Advarra IRB, Columbia, MD) except for one site that required a local IRB (Committee on the Protection of Human Subjects, Providence, RI). Reporting of data for this study adheres to CONSORT guidelines. Consent to participate: The purpose and nature of the study, as well as the possibility of adverse effects, were explained to study participants in understandable plain language terms, and written informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: P.N.G., D.W., S.K.B., and K.D. are employees of Akebia Therapeutics, Inc., and A.C. is a former employee of Akebia Therapeutics, Inc.

Figures

Fig. 1
Fig. 1
Study design. (a) Patients in the vadadustat groups did not receive a dose of ESA following randomization or for the duration of the 10-day treatment period. The ESA washout period started from the time of the last ESA dose prior to randomization, which may have included day of randomization. (b) Patients began their 10-day treatment period within 36 days of initiating screening. Day 1 occurred after a short interdialytic period at the earliest in-clinic visit following randomization. (c) Patients who completed the 10-day treatment period had a follow-up visit 2 days (+3) after Day 10. Patients who discontinued treatment early had a follow-up visit 2 days (+3) after their end-of-treatment visit. ESA, erythropoiesis-stimulating agent
Fig. 2
Fig. 2
Mean plasma concentration-time profile for vadadustat (µg/mL) on Day 1 and Day 8. Error bars indicate 95% CI; geometric mean values were used for vadadustat concentration calculations. Samples were collected on Day 1 and Day 8 during dialysis. h, hours
Fig. 3
Fig. 3
Mean plasma concentration-time profile for vadadustat-OG (µg/mL) on Day 1 and Day 8. Error bars indicate 95% CI; geometric mean values were used for vadadustat concentration calculations. h, hours
Fig. 4
Fig. 4
Mean and fold-change EPO concentration-time profile (mU/mL) in the vadadustat treatment group. Error bars indicate 95% CI. EPO, erythropoietin; h, hours
Fig. 5
Fig. 5
Mean and fold-change EPO concentration (mU/mL) in the ESA treatment group. Error bars indicate 95% CI. EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; h, hours
Fig. 6.
Fig. 6.
Mean and fold-change reticulocytes, hemoglobin, and RBC concentrations in the vadadustat and ESA treatment groups. Error bars indicate 95% CI. ESA, erythropoiesis-stimulating agent; h, hours; RBC, red blood cell
See this image and copyright information in PMC

References

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