Iwasaki Mami, Yano Ikuko, Fukatsu Sachio, Hashi Sachiyo, Yamamoto Yuki, Sugimoto Mitsuhiro, Fukudo Masahide, Masuda Satohiro, Nakagawa Shunsaku, Yonezawa Atsushi, Kaido Toshimi, Uemoto Shinji, Matsubara Kazuo
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan. Dr. Fukudo is now with the Department of Pharmacy and Pharmacology, Asahikawa Medical University, Japan. Dr. Masuda is now with the Department of Pharmacy, Kyushu University Hospital, Japan.
Department of Clinical Trial Management, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
Ther Drug Monit. 2018 Dec;40(6):675-681. doi: 10.1097/FTD.0000000000000551.
This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation.
Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation.
The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC0-24 in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups.
The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC0-24. If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.
本研究调查了活体肝移植（LDLT）术后早期使用他克莫司每日一次（OD）制剂的药代动力学和药效学，并与每日两次（TD）制剂进行比较。
纳入9例接受初次LDLT并使用他克莫司OD制剂治疗的患者。LDLT术后3周内每天监测他克莫司的谷血浓度（C0）。LDLT术后3周对外周血单核细胞中的他克莫司血药浓度和钙调神经磷酸酶（CN）磷酸酶活性进行了时间进程研究。将药代动力学和药效学参数与先前报道的使用TD制剂的数据进行比较。
他克莫司每日剂量的个体间变异性在OD制剂中显著大于TD制剂（P < 0.001）。在时间进程研究中，OD组给药后4、8和12小时的他克莫司血药浓度以及0至24小时的浓度-时间曲线下面积（AUC0-24）显著高于TD组，尽管C0相当。此外，OD制剂中C0与AUC0-24无显著相关性。OD组和TD组之间的表观清除率和所检测的药效学参数无显著差异。
LDLT术后早期患者中，OD制剂的C0监测可能并非最佳选择，因为C0与AUC0-24不相关。如果临床医生使用OD和TD制剂时将C0设定为相同目标，OD制剂中他克莫司的暴露量可能更高，应注意过度免疫抑制。在使用他克莫司OD口服制剂时，LDLT术后早期患者应格外注意。
