Laille Eric, Goel Sanjay, Mita Alain C, Gabrail Nashat Y, Kelly Kevin, Liu Liangang, Songer Stephen, Beach Charles L
Pharmacotherapy. 2014 May;34(5):440-51. doi: 10.1002/phar.1371.
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.
Multicenter, phase I, open-label, parallel group study.
Community clinics and major academic centers.
Twenty-seven patients with solid or hematologic malignancies.
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.
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.
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.
评估单次皮下注射25 - 100mg/m²阿扎胞苷后其药代动力学（PK）的剂量比例关系，并确定肾功能损害对单次及多次皮下注射75mg/m²阿扎胞苷后PK的影响。
多中心、I期、开放标签、平行组研究。
社区诊所和主要学术中心。
27例实体或血液系统恶性肿瘤患者。
第1部分评估肾功能正常的患者随机接受单次皮下注射25、50、75或100mg/m²阿扎胞苷后的剂量比例关系。75mg/m²给药组额外接受4天的皮下注射阿扎胞苷。在第2部分，严重肾功能损害（肌酐清除率<30ml/min/1.73m²，根据Cockcroft - Gault公式校正）的患者连续5天接受75mg/m²阿扎胞苷治疗。
采用非房室模型方法确定PK参数。在肾功能正常的患者（n = 21）中，阿扎胞苷的血浆-时间曲线下面积（AUC0-∞）和最大观察血浆浓度（Cmax）在25 - 100mg/m²范围内呈剂量比例关系。单次及多次皮下注射75mg/m²阿扎胞苷后，肾功能正常（n = 6）或受损（n = 6）患者的浓度-时间曲线形状相似，后者的平均浓度较高。观察到肾功能受损患者的平均暴露量（AUC0-∞和Cmax）较高；然而，除少数例外，两组患者的个体暴露值在同一范围内。两组均未观察到多次给药后的药物蓄积。两组的末端半衰期和达最大血浆浓度时间相当。肾功能正常或受损患者的阿扎胞苷耐受性相似。
阿扎胞苷在25 - 100mg/m²给药范围内呈剂量比例关系。总体而言，肾功能损害对阿扎胞苷的PK无重要影响。因此，肾功能受损患者无需初始调整阿扎胞苷剂量。
