他克莫司在儿童肾病综合征群体中的治疗药物监测

李玲, 郭宏丽, 胡雅慧, 李运曼, 方伟蓉, 赵非, 许静, 陈峰

中国药学杂志 ›› 2021, Vol. 56 ›› Issue (23) : 1880-1886.

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中国药学杂志
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中国药学杂志 ›› 2021, Vol. 56 ›› Issue (23) : 1880-1886. DOI: 10.11669/cpj.2021.23.003
综述

他克莫司在儿童肾病综合征群体中的治疗药物监测

  • 李玲1a,2, 郭宏丽1a, 胡雅慧1a, 李运曼2, 方伟蓉2, 赵非1b, 许静1a, 陈峰1a*
作者信息 +

Therapeutic Drug Monitoring of Tacrolimus in Children with Nephrotic Syndrome

  • LI Ling1a,2, GUO Hong-li1a, HU Ya-hui1a, LI Yun-man2, FANG Wei-rong2, ZHAO Fei1b, XU Jing1a, CHEN Feng1a*
Author information +
文章历史 +

摘要

他克莫司是肾病综合征患儿的二线治疗药物。然而其治疗窗狭窄,血药浓度在个体间和个体内的差异较大,为临床安全合理应用带来了挑战。因此,笔者回顾了国内外关于他克莫司血药浓度的影响因素及其在肾病综合征患儿中应用的相关研究,探讨其在治疗过程中应维持的目标浓度。他克莫司的药动学过程受到了生理病理、联合用药、饮食和药物代谢酶遗传多态性等多种因素的影响。他克莫司的最佳血药浓度范围存在着争议,关于谷浓度与疗效及不良反应相关性的研究较少,但近几年不断有研究指出,低于5~10 ng·mL-1的目标谷浓度对于肾病综合征的治疗仍然有效。考虑到他克莫司血药浓度影响因素众多,临床应通过治疗药物监测以调整给药剂量,但关于目标治疗浓度仍有待质量高的临床试验进一步研究。

Abstract

Tacrolimus (TAC), a calcineurin inhibitor, has been widely used as a second-line immunosuppressant for the treatment of children with nephrotic syndrome. However, the narrow therapeutic window and the wide inter-individual pharmacokinetic (PK) variability of TAC are hidden troubles for clinical application. The published articles regarding the contributing factors of TAC plasma concentration and the application of TAC in children with nephrotic syndrome were reviewed, and the ideal range of TAC concentration was discussed. Oral TAC is rapidly absorbed, while the bioavailability is low. The PK is affected by physiopathology, co-medications, diet, genetic polymorphism of drug metabolizing enzymes and other factors. Studies on the correlation between TAC concentration and efficacy were few, and the optimal range of concentration is controversial. Recent years, it has been pointed out that the target valley concentration below 5-10 ng·mL-1 is still effective for the treatment of nephrotic syndrome. Therapeutic drug monitoring is still needed to adjust the dose of the TAC, while the target therapeutic concentration remains to be further studied in high quality clinical trials.

关键词

他克莫司 / 肾病综合征 / 血药浓度 / 治疗药物监测 / 基因多态性

Key words

tacrolimus / nephrotic syndrome / blood concentration / therapeutic drug monitoring / genetic polymorphism

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李玲, 郭宏丽, 胡雅慧, 李运曼, 方伟蓉, 赵非, 许静, 陈峰. 他克莫司在儿童肾病综合征群体中的治疗药物监测[J]. 中国药学杂志, 2021, 56(23): 1880-1886 https://doi.org/10.11669/cpj.2021.23.003
LI Ling, GUO Hong-li, HU Ya-hui, LI Yun-man, FANG Wei-rong, ZHAO Fei, XU Jing, CHEN Feng. Therapeutic Drug Monitoring of Tacrolimus in Children with Nephrotic Syndrome[J]. Chinese Pharmaceutical Journal, 2021, 56(23): 1880-1886 https://doi.org/10.11669/cpj.2021.23.003
中图分类号： T969.3   

参考文献

[1] GUO H L, LI L, XU Z Y, et al. Steroid-resistant nephrotic syndrome in children: A mini-review on genetic mechanisms, predictive biomarkers and pharmacotherapy strategies. Curr Pharm Des, 2021,27(2):319-329.
[2] LOMBEL R M, HODSON E M, GIPSON D S, et al. Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO. Pediatr Nephrol, 2013, 28(3):409-414.
[3] SUN J Y, GUO H L, XU J. Application of calcineurin inhibitor in children with refractory nephrotic syndrome. Chin J New Drug(中国新药杂志), 2018, 27(13):1515-1520.
[4] GULATI S, PRASAD N, SHARMA R K, et al. Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant, 2008, 23(3):910-913.
[5] LI L, GUO H L, GUO H L, et al. Individualized treatment of children with primary membranous nephropathy. J Nanjing Med Univ(Nat Sci), 2020, 40(9):1403-1406.
[6] HAO G X, SONG L L, ZHANG D F, et al. Off-label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics. Br J Clin Pharmacol, 2020, 86(2):274-284.
[7] ERICSON J E, ZIMMERMAN K O, GONZALEZ D, et al. A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation. Ther Drug Monit, 2017, 39(1):13-20.
[8] BRUNET M, VAN GELDER T, ASBERG A, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report. Ther Drug Monit, 2019, 41(3):261-307.
[9] SHUKER N, VANn GELDER T, HESSELINK D A. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. Transplant Rev (Orlando), 2015, 29(2):78-84.
[10] BARBARINO J M, STAATZ C E, VENKATARAMANAN R, et al. PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet Genomics, 2013, 23(10):563-85.
[11] KAMDEM L K, STREIT F, ZANGER U M, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem, 2005, 51(8):1374-81.
[12] SUN J Y, XU Z J, SUN F, et al. Individualized tacrolimus therapy for pediatric nephrotic syndrome: considerations for ontogeny and pharmacogenetics of CYP3A. Curr Pharm Des, 2018, 24(24):2765-2773.
[13] STAATZ C E, TETT S E. Clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Clin Pharmacokinet, 2015, 54(10):993-1025.
[14] YU M, LIU M, ZHANG W, et al. Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation. Curr Drug Metab, 2018, 19(6):513-522.
[15] WANG X, HAN Y, CHEN C, et al. Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome. Int J Clin Pharmacol Ther, 2019, 57(3):125-134.
[16] HUANG L, LIU Y, JIAO Z, et al. Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis-Menten pharmacokinetic model. Eur J Pharm Sci, 2020, 143:105199.
[17] CHEN X, WANG D D, XU H, et al. Optimization of initial dosing scheme of tacrolimus in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule. Xenobiotica, 2020, 50(5):606-613.
[18] LU T, ZHU X, XU S, et al. Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome. Pharm Res, 2019, 36(3):45.
[19] HUANG L F, ZHAO C Y, JIAO Z, et al. Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome. Acta Pharm Sin(药学学报), 2018, 53(2):263-270.
[20] MURRY D J, CROM W R, REDDICK W E, et al. Liver volume as a determinant of drug clearance in children and adolescents. Drug Metab Dispos, 1995, 23(10):1110-1116.
[21] GUO H L, XU J, SUN J Y, et al. Tacrolimus treatment in childhood refractory nephrotic syndrome: a retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels. Int Immunopharmacol, 2020, 81:106290.
[22] WANG D, LU J, LI Q, et al. Population pharmacokinetics of tacrolimus in pediatric refractory nephrotic syndrome and a summary of other pediatric disease models. Exp Ther Med, 2019, 17(5):4023-4031.
[23] LU Y X, SU Q H, WU K H, et al. A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients. Acta Pharmacol Sin(中国药理学报), 2015, 36(2):281-288.
[24] ZHOU Y, ZHOU B, LV F J, et al. Analysis of influence factors of tacrolimus concentration in pediatric patients with nephrotic syndrome. Chin J New Drug(中国新药杂志), 2019, 28(18):2299-2304.
[25] BLAKE M J, CASTRO L, LEEDER J S, et al. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med, 2005, 10(2):123-38.
[26] GAO P, GUAN X L, HUANG R, et al. Risk factors and clinical characteristics of tacrolimus-induced acute nephrotoxicity in children with nephrotic syndrome: a retrospective case-control study. Eur J Clin Pharmacol, 2020, 76(2):277-284.
[27] STANKE-LABESQUE F, GAUTIER-VEYRET E, CHHUN S, et al. Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment. Pharmacol Ther, 2020,215:107627.
[28] LI N, LIU N, TANG S, et al. Pharmaceutical Practice of Individualized Treatment for a Patient after Lung Transplantation by Clinical Pharmacist. Chin Pharm J(中国药学杂志), 2019, 54(10):834-838.
[29] DU W W, WANG X X, ZHANG D, et al. Analysis of Influential Parameters on Tacrolimus Dosage and Concentration One Year after Lung Transplantation. Chin Pharm J(中国药学杂志), 2020, 55(15):1310-1315.
[30] KNOPS N, LEVTCHENKO E, VAN DEN HEUVEL B, et al. From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation. Int J Pharm, 2013, 452(1-2):14-35.
[31] BIRDWELL K A, DECKER B, BARBARINO J M, et al. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther, 2015, 98(1):19-24.
[32] LESCHE D, SIGURDARDOTTIR V, SETOUD R, et al. CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients. Ther Drug Monit, 2014, 36(6):710-715.
[33] STAATZ C E, GOODMAN L K, TETT S E. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet, 2010, 49(3):141-75.
[34] LI H, LAMPE J N. Neonatal cytochrome P450 CYP3A7: a comprehensive review of its role in development, disease, and xenobiotic metabolism. Arch Biochem Biophys, 2019, 673:108078.
[35] TURNER R M, FONTANA V, ZHANG J E, et al. A Genome-wide Association Study of Circulating Levels of Atorvastatin and Its Major Metabolites. Clin Pharmacol Ther, 2020, 108(2):287-297.
[36] LIU H, XU Q, HUANG W, et al. CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Eur J Clin Pharmacol, 2019, 75(11):1533-1540.
[37] RIEGERSPERGER M, PLISCHKE M, STEINHAUSER C, et al. The effect of ABCB1 polymorphisms on serial tacrolimus concentrations in stable austrian long-term kidney transplant recipients. Clin Lab, 2016, 62(10):1965-1972.
[38] LIU Y Y, LI C, CUI Z, et al. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis. Gene, 2013, 531(2):476-488.
[39] LI Y, YAN L, SHI Y Y, et al. CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients. Springerplus, 2015, 4(1):637.
[40] AQUILANTE C L, NIEMI M, GONG L, et al. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8. Pharmacogenet Genomics, 2013, 23(12):721-728.
[41] MIN S I, KIM S Y, AHN S H, et al. CYP3A5*1 allele: impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation, 2010, 90(12):1394-400.
[42] DE JONGE H, DE LOOR H, VERBEKE K, et al. In vivo CYP3A4 activity, CYP3A5 genotype, and hematocrit predict tacrolimus dose requirements and clearance in renal transplant patients. Clin Pharmacol Ther, 2012, 92(3):366-375.
[43] MO X, LI J, LIU Y, et al. Kidney podocyte-associated gene polymorphisms affect tacrolimus concentration in pediatric patients with refractory nephrotic syndrome. Pharmacogenomics J, 2020, 20(4):543-552.
[44] FAN J, ZHANG X, REN L, et al. Donor IL-18 rs5744247 polymorphism as a new biomarker of tacrolimus elimination in Chinese liver transplant patients during the early post-transplantation period: results from two cohort studies. Pharmacogenomics, 2015, 16(3):239-250.
[45] LIU M Z, HE H Y, ZHANG Y L, et al. IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacol Sin(中国药理学报), 2017, 38(3):415-423.
[46] LI C J, LI L, LIN L, et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS One, 2014, 9(1):e86206.
[47] SEYHUN Y, CIFTCI H S, KEKIK C, et al. Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-beta, tumour necrosis factor-alpha and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients. Int J Immunogenet, 2015, 42(3):147-160.
[48] DICKMANN L J, PATEL S K, WIENKERS L C, et al. Effects of interleukin 1beta (IL-1beta) and IL-1beta/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Curr Drug Metab, 2012, 13(7):930-937.
[49] CHEN L, PRASAD G V R. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. Pharmgenomics Pers Med, 2018, 11:23-33.
[50] DENG R, LIAO Y, LI Y, et al. Association of CYP3A5, CYP2C8, and ABCB1 polymorphisms with early renal injury in Chinese liver transplant recipients receiving tacrolimus. Transplant Proc, 2018, 50(10):3258-3265.
[51] HOU Q, HAN W, FU X. Pharmacokinetic interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome. Eur J Clin Pharmacol, 2013, 69(10):1861-1862.
[52] YUAN M, ZHANG Y. The effects of Chinese traditional medicine, Chinese traditional medicine ingredient and common food on tacrolimus blood concentration. Drugs Eval(药品评价), 2013, 10(16):20-24.
[53] SUN J Y, HU Y H, GUO H L, et al. Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis. Eur J Clin Pharmacol, 2019, 75(4):591-593.
[54] ZHU K Q, WANG Y, GE G J, et al. Effect of Wuzhi capsules on serum concentration of tacrolimus and liver and kidney function in patients with refractory nephrotic syndrome. China Med(中国医药), 2020, 15(5):726-729.
[55] CAI Y P, CHEN Q J, XIE P H, et al. Effect of wuzhi capsules on the blood concentration of tacrolimus relative to diltiazem and CYP3A5 gene polymorphisms. Acta Pharm Sin(药学学报), 2020, 55(2):272-275.
[56] ZHAI X, CHEN C, XU X, et al. Marked change in blood tacrolimus concentration levels due to grapefruit in a renal transplant patient. J Clin Pharm Ther, 2019, 44(5):819-822.
[57] VISCHINI G, NISCOLA P, STEFONI A, et al. Increased plasma levels of tacrolimus after ingestion of green tea. Am J Kidney Dis, 2011, 58(2):329.
[58] WANG J, GAO P, ZHANG H, et al. Evaluation of concentration errors and inappropriate dose tailoring of tacrolimus caused by sampling-time deviations in pediatric patients with primary nephrotic syndrome. Ther Drug Monit, 2020, 42(3):392-399.
[59] ZHOU H, ZHANG J, WU S L, et al. Associations of CYP3A4 /5 and POR Polymorphisms with Tacrolimus Concentrations in Chinese Adult Heart Transplant Recipients. Chin Pharm J(中国药学杂志), 2017, 52(19):1710-1714.
[60] TERENTE M P. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl, 2012, 2(2):163-171.
[61] PENNESI M, GAGLIARDO A, MINISINI S. Effective tacrolimus treatment in a child suffering from severe nephrotic syndrome. Pediatr Nephrol, 2003, 18(5):477-478.
[62] BHIMMA R, ADHIKARI M, ASHARAM K, et al. Management of steroid-resistant focal segmental glomerulosclerosis in children using tacrolimus. Am J Nephrol, 2006, 26(6):544-551.
[63] LOEFFLER K, GOWRISHANKAR M, YIU V. Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr Nephrol, 2004, 19(3):281-287.
[64] BUTANI L, RAMSAMOOJ R. Experience with tacrolimus in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol, 2009, 24(8):1517-1523.
[65] WANG J, MAO J, CHEN J, et al. Evaluation of mycophenolate mofetil or tacrolimus in children with steroid sensitive but frequently relapsing or steroid-dependent nephrotic syndrome. Nephrology (Carlton), 2016, 21(1):21-27.
[66] CHOUDHRY S, BAGGA A, HARI P, et al. Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. Am J Kidney Dis, 2009, 53(5):760-769.
[67] ROBERTI I, VYAS S. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol, 2010, 25(6):1117-1124.
[68] GULATI A, SINHA A, GUPTA A, et al. Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int, 2012, 82(10):1130-1135.
[69] SAMUEL S, BITZAN M, ZAPPITELLI M, et al. Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children. Am J Kidney Dis, 2014, 63(3):354-362.
[70] BASU B, SANDER A, ROY B, et al. Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial. JAMA Pediatr, 2018, 172(8):757-764.
[71] CHEN H X, CHENG Q, LI F, et al. Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome. World J Pediatr, 2020, 16(2):159-167.
[72] JAHAN A, PRABHA R, CHATURVEDI S, et al. Clinical efficacy and pharmacokinetics of tacrolimus in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol, 2015, 30(11):1961-1967.
[73] KIM J, PATNAIK N, CHORNY N, et al. Second-line immunosuppressive treatment of childhood nephrotic syndrome: a single-center experience. Nephron Extra, 2014, 4(1):8-17.
[74] GAO P, GUAN X L, LIU X, et al. Research of the therapetic window concentration of tacrolimus in pediatric nephrotic syndrome. Chin J Hosp Pharm(中国医院药学杂志), 2020, 40(1):59-64.
[75] PERYSINAKI G S, MOYSIADIS D K, BERTSIAS G, et al. Podocyte main slit diaphragm proteins, nephrin and podocin, are affected at early stages of lupus nephritis and correlate with disease histology. Lupus, 2011, 20(8):781-791.
[76] AGRAWAL V, PRASAD N, JAIN M, et al. Reduced podocin expression in minimal change disease and focal segmental glomerulosclerosis is related to the level of proteinuria. Clin Exp Nephrol, 2013, 17(6):811-818.
[77] RAMACHANDRAN R, KUMAR V, RATHI M, et al. Tacrolimus therapy in adult-onset steroid-resistant nephrotic syndrome due to a focal segmental glomerulosclerosis single-center experience. Nephrol Dial Transplant, 2014, 29(10):1918-1924.
[78] KANEKO T, FUJIOKA T, SUZUKI Y, et al. Comparison of whole-blood tacrolimus concentrations measured by different immunoassay systems. J Clin Lab Anal, 2018, 32(9):e22587.
[79] MIURA M, MASUDA S, EGAWA H, et al. Inter-laboratory variability of current immunoassay methods for tacrolimus among japanese hospitals. Biol Pharm Bull, 2016, 39(8):1331-1337.
[80] O′REGAN J A, CANNEY M, CONNAUGHTON D M, et al. Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation. J Nephrol, 2016, 29(2):269-276.
[81] RAYAR M, TRON C, JEZEQUEL C, et al. High intrapatient variability of tacrolimus exposure in the early period after liver transplantation is associated with poorer outcomes. Transplantation, 2018, 102(3):e108-e114.
[82] BREMER S, VETHE NT, SKAUBY M, et al. NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. Br J Clin Pharmacol, 2017, 83(11):2494-2502.
[83] STEINEBRUNNER N, SANDIG C, SOMMERER C, et al. Reduced residual gene expression of nuclear factor of activated T cells-regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation. Transpl Infect Dis, 2014, 16(3):379-386.
[84] CAPRON A, LERUT J, LATINNE D, et al. Correlation of tacrolimus levels in peripheral blood mononuclear cells with histological staging of rejection after liver transplantation: preliminary results of a prospective study. Transpl Int, 2012, 25(1):41-47.
[85] TRON C, WOILLARD J B, HOUSSEL-DEBRY P, et al. Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients. PLoS One, 2020, 15(3):e0230195.

基金

江苏卫生健康委员会特聘医学专家项目(2019);南京市卫生科技发展专项基金项目资助(YKK1147);江苏省药学会-奥赛康医院药学基金资助项目(A201606,A201810)
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