Population pharmacokinetics of Jesduvroq (daprodustat) in chronic kidney disease patients with anemia
Sebastiaan C. Goulooze (1), Shuying Yang (2), Emir Mesic (1), Misba Beerahee (2), Teun M. Post (1), Kelly M. Mahar (3)
(1) Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands, (2) Clinical Pharmacology Modelling and Simulation, GSK, London, UK, (3) Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, PA, USA
Objectives: Jesduvroq (daprodustat) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). It is approved for the treatment of anemia in adult patients with chronic kidney disease (CKD) in Japan. Furthermore, it has been approved in the United States (US) for the treatment of anemia in adult patients who have been receiving dialysis for at least four months. The aim of the current pharmacokinetic analysis was to further characterize the population pharmacokinetics (PK) of daprodustat and investigate the influence of covariates on the pharmacokinetics in patients with CKD in one US-based phase 2b study and four global phase 3 studies.
Methods: Initially, a three-compartment population PK model with four or seven absorption transit compartments depending on food intake characterized the PK in a total of twelve phase 1 and eight phase 2 studies, where daprodustat was given intravenously either once a day (QD), twice daily (BID), or three times weekly (TIW), with oral doses ranging from 0.5 to 600 mg. This earlier developed model was thereafter applied to describe the Japanese phase 3 (three studies, 1–24 mg QD) population, to further characterize the PK, and to investigate the effects of covariates[1]. Subsequently, this population PK model was applied to the data from the global phase 3 program (1–24 mg QD, and 2–48 mg TIW), followed by a stepwise covariate analysis. Finally, forest plots and typical simulations were created to illustrate the impact of covariates on the daprodustat exposure metrics (AUC and Cmax).
Results: A total of 4096 daprodustat PK observations across 707 patients were available for analysis from the current five phase 2b/3 studies. The final model characterizing the PK of daprodustat is described by a three-compartment distribution with first-order elimination and five absorption transit compartments. Minor modifications were done to the model structure to capture the current data (eg, removal of a saturable absorption component needed for high phase 1 doses [above 300 mg] outside the clinical dosing range). In addition to bodyweight (which was included with fixed allometric exponents of 0.75 on clearance terms and 1.0 on volumes relative to a 70-kg subject), two significant covariates were identified: the concomitant use of clopidogrel reduced clearance by 42.4%, and patients that were nondialysis–dependent had a 45.6% higher oral absorption rate compared to dialysis-dependent patients. From the typical simulations, the influence of the covariate effects on daprodustat exposure were visualized: dialysis (no change in AUC and −14% in Cmax) and concomitant clopidogrel use (+74% AUC and +18% Cmax).
Conclusions: The observed pharmacokinetics of daprodustat in the single phase 2b study and the four global phase 3 studies were well described with the final population PK model. This model was sequentially and incrementally updated relative to the population PK model characterizing the PK of the available phase 1, 2, and 3 (Japanese studies) data. Finally, the impact of covariates on daprodustat exposure metrics in the phase 3 studies was quantified.
References:
[1] Mahar K et al. Clin Pharm Therap 2021;109:S5–88. Abstract PI-031.