Clinical Pharmacology Service, La Paz University Hospital, Madrid, Spain; Department of Pharmacology, School of Medicine, Autonomous University of Madrid, Madrid, Spain.
Liver Transpl. 2013 Oct;19(10):1151-8. doi: 10.1002/lt.23711.
The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.
将 Advagraf 用于从 Prograf 转换的推荐剂量被认为是基于毫克的 1:1。然而，Prograf 和 Advagraf 的长期等效性一直存在争议。在一项单中心、开放性研究中，评估了 20 名年龄在 12 至 18 岁之间的稳定肝移植患者从 Prograf 转换为 Advagraf 的情况。在接受 Prograf 监督治疗 7 天后，患者转换为 Advagraf。在第 7 天和第 14 天，连续采集血样以测定他克莫司。采用非房室模型计算药代动力学参数，并根据标准统计方法计算两种制剂的相对生物利用度。采用标准方法确定细胞色素 P450 3A5(rs776746)、三磷酸腺苷结合盒 B1(rs1045642)、POR*28(rs1057868)和 POR(rs2868177)的多态性。收集所有患者转换后 30、90、180 和 360 天的 1 年随访期的临床和分析数据。Cmax 和 AUC0-24 的平均比值分别为 96.9(90%置信区间=85.37-110.19)和 100.1(90%置信区间=90.8-112.1)。患者的基因型与药代动力学他克莫司值之间没有关系。在随访期间，生化参数(天冬氨酸氨基转移酶、丙氨酸氨基转移酶、胆红素、胱抑素 C 和肌酐)没有明显变化;3 名患者出现相关临床事件，但没有事件被认为与他克莫司有关。转换后 3 个月和 6 个月时观察到他克莫司血药水平下降和剂量/水平比值增加，但到第 12 个月时恢复到基础水平。总之，以 1:1 剂量等效性从 Prograf 转换为 Advagraf 作为初始指南是合适的。我们的 1 年随访显示他克莫司水平短暂下降，因此转换后可能需要更密切地监测他克莫司水平。
