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 25-100mg/m(2), and determine the effect of renal impairment on PK after single and multiple 75mg/m(2) 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 100mg/m(2) SC doses. The 75mg/m(2) dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance <30ml/min/1.73m(2) Cockcroft-Gault adjusted) received azacitidine 75mg/m(2) 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 (AUC(0-infinity)) and maximum observed plasma concentration (C-max) were dose proportional within the 25-100mg/m(2) range. Concentration versus time profiles after single and multiple azacitidine 75mg/m(2) 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 (AUC(0-infinity) and C-max) 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 25-100mg/m(2) 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.