Early application of tacrolimus extended-release capsule after kidney transplantation
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摘要:
目的 探讨肾移植术后早期应用他克莫司缓释胶囊(Tac-ER)的有效性及安全性。 方法 回顾性分析接受34对供肾所行肾移植的68例受者临床资料,接受同一供者两侧肾脏的2例受者术后分别采用Tac-ER(Tac-ER组)和他克莫司胶囊(Tac-IR)(Tac-IR组)作为基础免疫抑制药之一。比较两组他克莫司剂量及血药浓度变化、药物浓度个体内变异度(IPV)、肾功能、急性排斥反应发生率、受者和移植物存活率、不良事件发生情况。 结果 Tac-ER组的平均他克莫司日剂量高于Tac-IR组(F=8.386,P=0.005)。Tac-ER组术后4 d平均谷浓度未达目标浓度,为(6.14±4.04)ng/mL,低于Tac-IR组的(9.41±5.47)ng/mL(F=7.854,P=0.007)。Tac-ER组术后1个月内他克莫司谷浓度IPV高于Tac-IR组(0.44±0.15比0.36±0.12,P=0.032)。术后第6个月时,Tac-ER组和Tac-IR组肾功能比较差异无统计学意义[血清肌酐为(126±26)μmol/L比(120±28)μmol/L,估算肾小球滤过率为(56±13)mL/(min·1.73 m2)比(60±15)mL/(min·1.73 m2),均为P > 0.05]。两组移植物和受者存活率均为100%。Tac-ER组和Tac-IR组急性排斥反应均于术后1个月内发生,发生率分别为18%和3%,差异无统计学意义(P > 0.05)。Tac-ER组和Tac-IR组不良事件总发生率分别为94%和97%,差异无统计学意义(P > 0.05)。 结论 Tac-ER的有效性和安全性与Tac-IR相似,但需要口服更高剂量才能达到与Tac-IR相似的血药浓度。初始应用Tac-ER应在术前提前口服或以负荷剂量作为首剂量,以提高术后早期他克莫司的全身暴露量,预防暴露不足导致的急性排斥反应。 Abstract:Objective To evaluate the efficacy and safety of tacrolimus extended-release (Tac-ER) in the early stage after kidney transplantation. Methods Clinical data of 68 recipients undergoing kidney transplantation from 34 pairs of renal allografts were retrospectively analyzed. Two recipients who received bilateral kidneys from the same donor were treated with Tac-ER (Tac-ER group) and tacrolimus immediate-release (Tac-IR) (Tac-IR group) as one of the basic immunosuppressant. The changes of tacrolimus dosage and blood concentration, intra-patient variability (IPV), renal function, incidence of acute rejection, recipient and allograft survival rates and adverse events were statistically compared between two groups. Results The average daily dose of tacrolimus in the Tac-ER group was significantly higher than that in the Tac-IR group (F=8.386, P=0.005). In the Tac-ER group, the mean trough concentration at postoperative 4 d was (6.14±4.04) ng/mL, did not reach the target concentration, significantly lower than (9.41±5.47) ng/mL in the Tac-IR group (F=7.854, P=0.007). In the Tac-ER group, the IPV of trough concentration of tacrolimus within postoperative 1 month was significantly higher than that in the Tac-IR group (0.44±0.15 vs. 0.36±0.12, P=0.032). At postoperative 6 months, there was no significant difference in the renal function between two groups [serum creatinine level was (126±26) μmol/L vs. (120±28) μmol/L, and the estimated glomerular filtration rate was (56±13) mL/(min·1.73 m2) vs. (60±15) mL/(min·1.73 m2), both P > 0.05]. The allograft and recipient survival rates were 100% in both groups. The incidence of acute rejection within postoperative 1 month was 18% in the Tac-ER group and 3% in the Tac-IR group, with no significant difference (P > 0.05). The overall incidence of adverse events was 94% in the Tac-ER group and 97% in the Tac-IR group, with no significant difference (P > 0.05). Conclusions The efficacy and safety of Tac-ER are equivalent to those of Tac-IR, whereas a higher dose of Tac-ER should be orally given to reach the blood concentration similar to that of Tac-IR. During early-stage drug treatment, Tac-ER should be orally given before kidney transplantation or inittally with loading dose, aiming to increase the systemic exposure to tacrolimus early after kidney transplantation and prevent acute rejection caused by insufficient exposure. -
表 1 两组受者他克莫司谷浓度IPV比较
Table 1. Comparison of the IPV of tacrolimus trough concentration in recipients between two groups (x±s)
变量 Tac-ER组(n=34) Tac-IR组(n=34) P值 IPV 术后1个月 0.44±0.15 0.36±0.12 0.032 术后1~6个月 0.18±0.02 0.26±0.15 0.055 快代谢型IPV 术后1个月 0.43±0.15 0.32±0.10 0.015 术后1~6个月 0.11±0.07 0.24±0.10 0.007 慢代谢型IPV 术后1个月 0.45±0.15 0.39±0.13 0.307 术后1~6个月 0.19±0.08 0.27±0.15 0.190 -
[1] LENTINE KL, SMITH JM, HART A, et al. OPTN/SRTR 2020 annual data report: kidney[J]. Am J Transplant, 2022, 22(Suppl 2): 21-136. DOI: 10.1111/ajt.16982. [2] HART A, LENTINE KL, SMITH JM, et al. OPTN/SRTR 2019 annual data report: kidney[J]. Am J Transplant, 2021, 21(Suppl 2): 21-137. DOI: 10.1111/ajt.16502. [3] HART A, SMITH JM, SKEANS MA, et al. OPTN/SRTR 2018 annual data report: kidney[J]. Am J Transplant, 2020, 20(Suppl 1): 20-130. DOI: 10.1111/ajt.15672. [4] GONDOS A, DÖHLER B, BRENNER H, et al. Kidney graft survival in Europe and the United States: strikingly different long-term outcomes[J]. Transplantation, 2013, 95(2): 267-274. DOI: 10.1097/TP.0b013e3182708ea8. [5] NEUBERGER JM, BECHSTEIN WO, KUYPERS DR, et al. Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients: a guidance report and clinical checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) group[J]. Transplantation, 2017, 101(4S Suppl 2): S1-S56. DOI: 10.1097/TP.0000000000001651. [6] VADCHARAVIVAD S, SAENGRAM W, PHUPRADIT A, et al. Once-daily versus twice-daily tacrolimus in kidney transplantation: a systematic review and meta-analysis of observational studies[J]. Drugs, 2019, 79(18): 1947-1962. DOI: 10.1007/s40265-019-01217-7. [7] OH CK, BANG JB, KIM SJ, et al. Improvement of medication adherence with simplified once-daily immunosuppressive regimen in stable kidney transplant recipients: a prospective cohort study[J]. Asian J Surg, 2020, 43(6): 660-667. DOI: 10.1016/j.asjsur.2019.07.011. [8] HO B, BHAGAT H, SCHWARTZ JJ, et al. Real-world study of once-daily, extended-release tacrolimus versus twice-daily, immediate-release tacrolimus in kidney transplantation: clinical outcomes and healthcare resource utilization[J]. Adv Ther, 2019, 36(6): 1465-1479. DOI: 10.1007/s12325-019-00904-x. [9] SÁNCHEZ FRUCTUOSO A, RUIZ JC, FRANCO A, et al. Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: a retrospective study[J]. Clin Transplant, 2020, 34(1): e13767. DOI: 10.1111/ctr.13767. [10] LANG S, SHARMA A, FOSTER B, et al. Age and sex determine conversion from immediate-release to extended-release tacrolimus in a multi-center cohort of Canadian pediatric renal transplant recipients[J]. Pediatr Transplant, 2021, 25(5): e13959. DOI: 10.1111/petr.13959. [11] FERNANDEZ RIVERA C, CALVO RODRÍGUEZ M, POVEDA JL, et al. Bioavailability of once-daily tacrolimus formulations used in clinical practice in the management of de novo kidney transplant recipients: the better study[J]. Clin Transplant, 2022, 36(3): e14550. DOI: 10.1111/ctr.14550. [12] OBERBAUER R, BESTARD O, FURIAN L, et al. Optimization of tacrolimus in kidney transplantation: new pharmacokinetic perspectives[J]. Transplant Rev (Orlando), 2020, 34(2): 100531. DOI: 10.1016/j.trre.2020.100531. [13] VONDRAK K, PARISI F, DHAWAN A, et al. Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus[J]. Clin Transplant, 2019, 33(10): e13698. DOI: 10.1111/ctr.13698. [14] TABER DJ, POSADAS-SALAS A, SU Z, et al. Preliminary assessment of safety and adherence to a once-daily immunosuppression regimen in kidney transplantation: results of a randomized controlled pilot study[J]. Clin Transplant, 2020, 34(4): e13844. DOI: 10.1111/ctr.13844. [15] SAPIR-PICHHADZE R, WANG Y, FAMURE O, et al. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure[J]. Kidney Int, 2014, 85(6): 1404-1411. DOI: 10.1038/ki.2013.465. [16] TAN T, BUNNAPRADIST S. Comparing the pharmacokinetics of extended-release tacrolimus (LCP-TAC) to immediate-release formulations in kidney transplant patients[J]. Expert Opin Drug Metab Toxicol, 2021, 17(10): 1175-1186. DOI: 10.1080/17425255.2021.1974399. [17] SILVA HT JR, YANG HC, MEIER-KRIESCHE HU, et al. Long-term follow-up of a phase Ⅲ clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients[J]. Transplantation, 2014, 97(6): 636-641. DOI: 10.1097/01.TP.0000437669.93963.8E. [18] JANUARY SE, HAGOPIAN JC, NESSELHAUF NM, et al. Clinical experience with extended-release tacrolimus in older adult kidney transplant recipients: a retrospective cohort study[J]. Drugs Aging, 2021, 38(5): 397-406. DOI: 10.1007/s40266-021-00842-w. [19] HIRAMITSU T, TOMOSUGI T, FUTAMURA K, et al. Optimal blood levels of (extended-release) tacrolimus in living donor kidney transplantation to prevent de novo donor-specific antibody production: a retrospective cohort study[J]. Int Immunopharmacol, 2021, 91: 107038. DOI: 10.1016/j.intimp.2020.107038. [20] GUIRADO L, CANTARELL C, FRANCO A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients[J]. Am J Transplant, 2011, 11(9): 1965-1971. DOI: 10.1111/j.1600-6143.2011.03571.x. [21] HIDAKA Y, GOTO N, YAMANAGA S, et al. Two-year outcomes of low-exposure extended-release tacrolimus and mycophenolate mofetil regimen in de novo kidney transplantation: a multi-center randomized controlled trial[J]. Clin Transplant, 2022, 36(6): e14655. DOI: 10.1111/ctr.14655. [22] JASIAK-PANEK NM, WENZLER E, PATEL S, et al. A randomized, open-label pharmacokinetic trial of tacrolimus extended-release dosing in obese de novo kidney transplant recipients[J]. Clin Transplant, 2019, 33(8): e13640. DOI: 10.1111/ctr.13640. [23] KIM YH, CHIANG YJ, KIM SJ, et al. Safety and efficacy of reduced prolonged-release tacrolimus exposure in de novo kidney transplantation: a randomized, open-label, pilot study in Asia-OPTIMIZE study[J]. Transplant Direct, 2019, 5(4): e340. DOI: 10.1097/TXD.0000000000000877. [24] 王梓宇, 王洪阳, 王清海, 等. 转换使用他克莫司缓释胶囊对肾移植受者治疗有效性及安全性的影响[J]. 精准医学杂志, 2022, 37(5): 400-403. DOI: 10.13362/j.jpmed.202205006.WANG ZY, WANG HY, WANG QH, et al. Effect of conversion to tacrolimus sustained-release capsules on treatment efficacy and safety in kidney transplant recipients[J]. J Precis Med, 2022, 37(5): 400-403. DOI: 10.13362/j.jpmed.202205006. [25] POSADAS SALAS MA, SRINIVAS TR. Update on the clinical utility of once-daily tacrolimus in the management of transplantation[J]. Drug Des Devel Ther, 2014, 8: 1183-1194. DOI: 10.2147/DDDT.S55458. [26] DEL BELLO A, GAIBLE C, LONGLUNE N, et al. Tacrolimus intrapatient variability after switching from immediate or prolonged-release to extended-release formulation, after an organ transplantation[J]. Front Pharmacol, 2021, 12: 602764. DOI: 10.3389/fphar.2021.602764. [27] CASSUTO E, PAGEAUX GP, CANTAROVICH D, et al. Adherence to and acceptance of once-daily tacrolimus after kidney and liver transplant: results from OSIRIS, a French observational study[J]. Transplantation, 2016, 100(10): 2099-2106. DOI: 10.1097/TP.0000000000001307. [28] BUNTHOF KLW, AL-HASSANY L, NAKSHBANDI G, et al. A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients[J]. Clin Transl Sci, 2022, 15(4): 930-941. DOI: 10.1111/cts.13206. [29] STIFFT F, STOLK LM, UNDRE N, et al. Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation[J]. Transplantation, 2014, 97(7): 775-780. DOI: 10.1097/01.TP.0000437561.31212.0e. [30] XIE Q, XIANG Q, LIU Z, et al. Effects of CPY3A5 genetic polymorphisms on the pharmacokinetics of extended release and immediate-release tacrolimus formulations in renal transplant recipients: a systematic review and meta-analysis[J]. Curr Drug Metab, 2021, 22(10): 758-771. DOI: 10.2174/1389200222666210825160021. [31] THÖLKING G, FILENSKY B, JEHN U, et al. Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation[J]. Sci Rep, 2021, 11(1): 15606. DOI: 10.1038/s41598-021-95201-5. [32] 陈攀, 傅茜, 李晶洁, 等. CYP3 A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响[J]. 中国药理学通报, 2016, 32(11): 1592-1595. DOI: 10.3969/j.issn.1001-1978.2016.11.021.CHEN P, FU Q, LI JJ, et al. Impact of CYP3 A5 genetic polymorphism on modified releasing tacrolimus pharmacokinetics in Chinese renal transplant recipients[J]. Chin Pharm Bull, 2016, 32(11): 1592-1595. DOI: 10.3969/j.issn.1001-1978.2016.11.021. [33] 石丽娟, 胡津鹏, 陈妍, 等. CYP3A5基因多态性对肾移植受者他克莫司谷浓度及肾功能恢复的影响[J]. 中国处方药, 2022, 20(6): 22-24. DOI: 10.3969/j.issn.1671-945X.2022.06.010.SHI LJ, HU JP, CHEN Y, et al. Effects of CYP3A5 gene polymorphism on the trough concentration of tacrolimus and the recovery of renal function in renal transplant recipients[J]. J China Prescr Drug, 2022, 20(6): 22-24. DOI: 10.3969/j.issn.1671-945X.2022.06.010. [34] 王世磊, 丰贵文. 他克莫司缓释胶囊在CYP3A5不同基因型肾移植受者中浓度/剂量值的差异[J]. 河南医学研究, 2021, 30(15): 2708-2711. DOI: 10.3969/j.issn.1004-437X.2021.15.006.WANG SL, FENG GW. Differences of concentration/dose of tacrolimus sustained-release capsules in kidney transplant recipients with different CYP3A5 genotypes[J]. Henan Med Res, 2021, 30(15): 2708-2711. DOI: 10.3969/j.issn.1004-437X.2021.15.006. [35] 张恩瑶, 向倩, 谢秋芬, 等. CYP3A5基因多态性的他克莫司个体化用药临床研究分析[J]. 中国临床药理学杂志, 2022, 38(8): 864-868. DOI: 10.13699/j.cnki.1001-6821.2022.08.024.ZHANG EY, XIANG Q, XIE QF, et al. Clinical therapy analysis of individualized medication of tacrolimus based on CYP3 A5 gene polymorphism[J]. Chin J Clin Pharm, 2022, 38(8): 864-868. DOI: 10.13699/j.cnki.1001-6821.2022.08.024.