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 3 QUAZAR AML-001 study. The PopPK dataset comprised 286 patients with 1933 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 (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 (OR=5.71, 95% 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, versus 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.