Population pharmacokinetics of daprodustat across five phase 2b/3 studies in chronic kidney disease (CKD) patients with anemia
Objectives: Daprodustat is an oral drug currently approved for the treatment of anemia in patients with CKD in Japan. The aim of this analysis was to characterize the population pharmacokinetics (PK) of daprodustat and the influence of covariates in patients with CKD in one US-based phase 2b study and four global phase 3 studies.
Methods: A previously developed population PK model—three compartment, with four or seven absorption transit compartments depending on food intake—that characterized the PK in the Japanese phase 3 population was updated using the data from the global phase 3 program, followed by a stepwise covariate analysis. Forest plots and typical simulations were created to illustrate the impact of covariates on daprodustat exposure metrics (AUC and Cmax).
Results: A total of 4096 PK observations across 707 patients were available for analysis. The final model is described by three-compartment distribution with first-order elimination, and five absorption transit compartments. In addition to bodyweight (which was included with fixed allometric exponents), two significant covariates were identified: concomitant clopidogrel use reduced clearance by 42.4%, and patients that were non-dialysis–dependent had 45.6% higher oral absorption rate compared to dialysis-dependent patients. From typical simulations, the covariate effects on daprodustat exposure were: 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 global phase 3 studies were well described with the final population PK model and impact of covariates on daprodustat exposure metrics were quantified.
Author(s)
- Kelly M. Mahar, Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, Collegeville, Pennsylvania, USA (Presenting Author)
- Sebastiaan C. Goulooze, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)
- Shuying Yang, Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK (CoAuthor)
- Emir Mesic, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)
- Misba Beerahee, Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK (CoAuthor)
- Teun M. Post, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)