A phase I study in patients with solid or hematologic malignancies of the dose proportionality of subcutaneous Azacitidine and its pharmacokinetics in patients with severe renal impairment.

Study Objective: To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25-100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses.

Design: Multicenter, phase I, open-label, parallel group study.

Setting: Community clinics and major academic centers.

Patients: Twenty-seven patients with solid or hematologic malignancies.

Interventions: Part 1 evaluated azacitidine dose proportionality in patients with normal renal function randomized to single 25, 50, 75, or 100 mg/m2 SC doses. The 75 mg/m2 dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 Cockcroft-Gault adjusted) received azacitidine 75 mg/m2 for 5 consecutive days.

Measurements And Main Results: PK parameters were determined using noncompartmental methods. In patients with normal renal function (n=21), azacitidine area under the plasma-time curve (AUC0-∞) and maximum observed plasma concentration (Cmax) were dose proportional within the 25-100 mg/m2 range. Concentration versus time profiles after single and multiple azacitidine 75 mg/m2 doses were similar in shape for patients with normal (n=6) or impaired renal function (n=6), with higher mean concentrations in the latter group. Higher mean exposures (AUC0-∞ and Cmax) in renally impaired patients were observed; however, individual exposure values were, with few exceptions, within the same range in both groups. No drug accumulation after multiple doses was observed in either group. Terminal half-life and time to maximum plasma concentration were comparable between groups. Azacitidine tolerability was similar in patients with normal or impaired renal function.

Conclusion: Azacitidine is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK. Therefore, no initial azacitidine dose adjustment in patients with renal impairment is required.