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

作者：Laille Eric^*; Goel Sanjay; Mita Alain C; Gabrail Nashat Y; Kelly Kevin; Liu Liangang; Songer Stephen; Beach Charles L

来源：Pharmacotherapy, 2014, 34(5): 440-451.

DOI：10.1002/phar.1371

• solid tumor
• pharmacokinetics
• renal impairment
• myelodysplasia
• dose proportionality
• azacitidine

Study Objective %26lt;br%26gt;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. %26lt;br%26gt;Design %26lt;br%26gt;Multicenter, phase I, open-label, parallel group study. %26lt;br%26gt;Setting %26lt;br%26gt;Community clinics and major academic centers. %26lt;br%26gt;Patients %26lt;br%26gt;Twenty-seven patients with solid or hematologic malignancies. %26lt;br%26gt;Interventions %26lt;br%26gt;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 %26lt;30ml/min/1.73m(2) Cockcroft-Gault adjusted) received azacitidine 75mg/m(2) for 5 consecutive days. %26lt;br%26gt;Measurements and Main Results %26lt;br%26gt;PK parameters were determined using noncompartmental methods. In patients with normal renal 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 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. %26lt;br%26gt;Conclusion %26lt;br%26gt;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.

• 出版日期2014-5