Huub Jan Kleijn (1), Shinsuke Inoue (2), Megumi Furukawa (3), Rishikesh Sawant (4), Atsuhiro Kawaguchi (5), Ajit Chavan (6)
(1) Certara Inc., (2) Mitsubishi Tanabe Pharma Corp., (3) Mitsubishi Tanabe Pharma Corp., (4) Akebia Therapeutics, (5) Mitsubishi Tanabe Pharma Corp., (6) Akebia Therapeutics
Objectives: Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), is in late-stage development for the treatment of anemia in chronic kidney disease (CKD) [1]. Vadadustat inhibits HIF-PH thereby increasing endogenous erythropoiesis. A Japanese New Drug Application (JNDA) has been submitted for marketing approval of vadadustat. Vadadustat has been studied in patients with anemia due to CKD at a starting daily dose of 300 mg and dosing was adjusted between 150 and 600 mg daily based on hemoglobin response [2,3]. A moderate variability in pharmacokinetic (PK) exposures was observed. The aim of population PK (POPPK) modeling was to quantify the impact of intrinsic and extrinsic factors affecting the exposures of vadadustat in the patient population.
Methods: Vadadustat concentration data available from multiple studies with either intensive or sparse blood collection were included in the analysis. A structural model was built with intensive PK data collected from both healthy subjects after multiple dosing and patients after single dosing of vadadustat. The structural model incorporated body weight, estimated glomerular filtration rate (eGFR), and food intake as covariates. Upon inclusion of sparse PK data in CKD patients from Phase 2 and Japanese Phase 3 studies, covariate effects were investigated. Nonlinear mixed-effect modeling (NONMEM software version 7.3) was applied to the PK data, and model performance was evaluated using visual predictive check and goodness-of-fit plots. The post hoc estimations were used to predict the vadadustat exposures in CKD patients in the Phase 2 and Japanese Phase 3 studies and to further characterize and quantify the covariate effects.
Results: The POPPK analysis data set consisted of 678 subjects and was composed of 60 healthy volunteers, 327 non–dialysis-dependent (NDD) CKD patients, and 291 dialysis-dependent (DD) CKD patients. A model with a lag time and first-order oral absorption accurately described the pharmacokinetics of vadadustat. In the NDD-CKD and DD-CKD patient populations, geometric mean oral clearance (CL/F) values were 0.652 L/h (47.1% coefficient of variation [CV]) and 0.505 L/h (42.9% CV), respectively. The apparent steady-state distribution volume was estimated as 11.6 L (13.8% CV). PK parameters were allometrically scaled by body weight. Furthermore, lower eGFR was associated with a decrease in CL/F, and higher bilirubin was associated with decreased CL/F. Food impacted absorption of vadadustat, decreasing the absorption rate constant (ka) and increasing lag time, but did not affect bioavailability. Concomitant oral iron or non-iron phosphate binder usage marginally reduced the bioavailability of vadadustat. No effects of age, sex, race, ethnicity, liver enzymes (ALT, AST, albumin), or Japanese descent on CL/F were detected.
Conclusions: This is a first reported analysis to characterize the POPPK of the HIF-PHI class of molecules. In this assessment, vadadustat oral PK were well described by POPPK modeling, which adequately evaluated the intrinsic and extrinsic factors affecting PK. The estimation of individual exposures following post hoc analyses stratified by covariate subgroups further illustrated that body weight is the most important covariate for vadadustat exposure, and no substantial differences were observed in clearance of vadadustat in NDD-CKD and DD-CKD patient populations.
References:
[1] Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90(5):115-1122.
[2] Martin ER, Smith MT, Maroni BJ, Zuraw QC, deGoma EM. Clinical trial of vadadustat in patients with anemia secondary to stage 3 or 4 chronic kidney disease. Am J Nephrol. 2017;45(5):380-388.
[3] Haase VH, Chertow GM, Block GA, Pergola PE, deGoma EM, Khawaja Z, et al. Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulation agents. Nephrol Dial Transplant. 2019;34(1):90-99.
Reference: PAGE () Abstr 9453 [www.page-meeting.org/?abstract=9453]
Poster: Drug/Disease Modelling - Absorption & PBPK