Integrated Longitudinal Population Dose‐Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease

Daprodustat, a novel oral hypoxia‐inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose‐hemoglobin (Dose‐Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose‐titration algorithm, guided by simulations from the initial Dose‐Hgb model based on phase II clinical data, was implemented. This work was to update and re‐calibrate this model to support the dose titration algorithm. Data from five pivotal phase III studies in CKD patients with anemia treated with daprodustat once daily (q.d.) and/or three times a week (t.i.w.) using a titration dosing schedule were included. The data comprised 2,770 CKD patients with anemia providing 53,535 Hgb observations over a period of 6 months up to 4 years. This final Dose‐Hgb model consisted of a precursor cell compartment and 12 transit compartments to describe the red blood cell (RBC) lifespan. Treatment increased the precursor cell production rate ( K in ) by a power of allometrically scaled dose. Disease progression, as an exponential decline of Hgb production rate over time, varied with dialysis status. The dose‐titration algorithm resulted in comparable response for t.i.w. dosing relative to q.d. dosing. Titration‐based visual predictive checks for Hgb target criteria for the analysis dataset and the prediction dataset showed that the model adequately predicted the observed data. This re‐calibrated Dose‐Hgb model will provide further support for the individualized dosing strategy in CKD patients with anemia treated with daprodustat.