title: 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.
abstract: 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.
  
  
  METHODS
  Multicenter, phase I, open-label, parallel group study.
  
  
  METHODS
  Community clinics and major academic centers.
  
  
  METHODS
  Twenty-seven patients with solid or hematologic malignancies.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Eric
authors.initials: E
authors.lastname: Laille
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Nashat Y
authors.initials: NY
authors.lastname: Gabrail
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelly
authors.forename: Liangang
authors.initials: L
authors.lastname: Liu
authors.forename: Stephen
authors.initials: S
authors.lastname: Songer
authors.forename: Charles L
authors.initials: CL
authors.lastname: Beach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051437:Renal Insufficiency / Q000150:complications* / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine