Population Pharmacokinetics of Oral Azacitidine, and Exposure–Response Analysis in Acute Myeloid Leukemia

Oral azacitidine (oral‐AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post‐intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral‐AZA concentration–time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK‐estimated exposure parameters were used to evaluate exposure–response relationships in the phase III QUAZAR AML‐001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral‐AZA concentration records. The final PopPK model was a one‐compartment model with first‐order absorption incorporating an absorption lag time and first‐order elimination. Regression analyses identified two oral‐AZA exposure parameters (area under the plasma concentration–time curve at steady state (AUC ss ); maximum plasma concentration ( C max )) as statistically significant predictors for relapse‐free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUC ss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUC ss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73–12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76–4.44, P < 0.001), and C max at steady‐state (OR = 2.38, 95% CI = 1.23–4.76, P = 0.012). A decreasing trend was identified between AUC ss and relapse‐related schedule extensions, vs. an increasing trend between AUC ss and event‐related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral‐AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk.