目的 他克莫司是一种新型钙调磷酸酶抑制剂,目前被广泛应用于成人肝或肾移植术后,也被逐渐广泛应用于肾病综合征患儿。他克莫司缓释胶囊是每日单次口服的缓释剂型,本研究目的是初步探讨他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特征。方法 8例受试者系北京大学第一医院2011年6—8月原发性肾病综合征患儿。晨起单次口服不同剂量他克莫司缓释胶囊,给药剂量分别为0.02 mg/kg(n=2)、0.05 mg/kg(n=2)、0.10 mg/kg(n=4),在服药前及服药后1、2、4、6、8、10、12 h分别取静脉血1~2 mL,受试者不用影响他克莫司浓度的其他药物、食物及饮料。采用酶放大免疫分析法,测定他克莫司血药浓度,以Phoenix计算其药代动力学参数。结果 药代动力学数据采用非房室模型分析。3个剂量组(0.02 mg/kg,0.05 mg/kg和0.10 mg/kg)药代动力学参数如下:血药峰浓度分别为(1.7±1.0) μg/L,(3.1±1.9) μg/L,(8.0±3.5) μg/L;药物浓度-时间曲线下面积分别为(47.2±47.1) h·μg/L,(84.0±13.1) h·μg/L,(175.6±107.1) h·μg/L;表观清除率分别为(0.8±0.9) L/(h·kg),(0.4±0.1) L/(h·kg),(1.9±1.3) L/(h·kg);经剂量归一化的表观分布容积分别为(7.0±3.4) L/kg,(12.4±8.4) L/kg,(73.6±68.6) L/kg。0.05 mg/kg剂量组经剂量归一化的血药峰浓度和经剂量归一化的药物浓度-时间曲线下面积的平均值均高于0.02 mg/kg及0.10 mg/kg剂量组。3个剂量组的药物浓度-时间曲线均呈现2次高峰,第一次高峰出现在服药后约2 h,服药后约12 h出现次级高峰;0.10 mg/kg剂量组药物浓度出现两次峰值的现象较0.02 mg/kg及0.05 mg/kg剂量组更显著。结论 他克莫司缓释剂治疗原发性肾病综合征患儿的药代动力学存在个体间差异,本研究初步探讨了他克莫司缓释剂治疗儿童原发性肾病综合征的药代动力学特征,为后续大样本的研究提供了参考依据。
Objective: Tacrolimus prolonged-release(PR) formulation is a new once-daily formulation of the calcineurin inhibitor tacrolimus, which is currently used in adult liver or kidney transplant patients,and is also gradually widely used in children with nephrotic syndrome.The present study was undertaken to preliminarily investigate the pharmacokinetic characteristics of tacrolimus PR in pediatric nephrotic syndrome recipients. Methods: This single-center open-label prospective study was performed in pediatric nephrotic syndrome recipients. Pharmacokinetic samples were collected from eight pediatric subjects with nephrotic syndrome from Department of Pediatric Nephrology in Peking University First Hospital between June and August 2011. They followed administration of single oral doses of tacrolimus PR formulation at 0.02 mg/kg (n=2), 0.05 mg/kg (n=2) and 0.10 mg/kg (n=4). Blood samples were taken before the dose and 1, 2, 4, 6, 8, 10, 12 and 24 h after drug intake. No other medicines or interacting food or drinks were taken during the study period. Blood concentrations were measured using an enzyme multiplied immunoassay technique. Pharmacokinetic analysis was performed using WinNolin Phoenix software Version 6.0(Pharsight, Cary, NC,USA). Results: The pharmacokinetic data were best described by a non-compartment model. Pharmacokinetic parameters of tacrolimus PR formulation in the 3 ascending doses groups (0.02 mg/kg,0.05 mg/kg and 0.10 mg/kg) were as follows: the maximum drug concentrations (Cmax/D) were (1.7±1.0) μg/L, (3.1±1.9) μg/L, (8.0±3.5) μg/L, respectively;Areas under the drug concentration-time curve(AU0-∞/D) were (47.2±47.1) h·μg/L, (84.0±13.1) h·μg/L, (175.6±107.1) h·μg/L, respectively; Oral clearance rates were (0.8±0.9) L/(h·kg), (0.4±0.1) L/(h·kg), (1.9±1.3) L/(h·kg), respectively; Body weight normalized distribution volumes were (7.0±3.4) L/kg, (12.4±8.4) L/kg and (73.6±68.6) L/kg, respectively. Both mean Cmax normalized level for the administered dose(Cmax/D) and mean AU0-∞ normalized level for the administered dose (AU0-∞/D) were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage group. There were two peaks in the drug concentrations in every dose group;a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12, which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages. Conclusion: The pharmacokinetic characteristics of tacrolimus PR formulation were initially explored in pediatric patients with nephritic syndrome. The data presented form a basis for subsequent larger scale studies on pharmacokinetics of tacrolimus PR formulation in nephritic syndrome children.
[1] Abdulnour HA, Araya CE, Dharnidharka VR. Comparison of generic tacrolimus and Prograf drug levels in a pediatric kidney transplant program[J].Pediatr Transplant, 2010, 14(8):1007-1011.
[2] Holt DW, Armstrong VW, Griesmacher A, et al. Federation of clinical chemistry international association of therapeutic drug monitoring and clinical toxicology working group on immunosuppressive drug monitoring[J].Ther Drug Monit, 2002, 24(1):59-67.
[3] Zhao W, Fakhoury M, Baudouin V, et al.Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients[J].Eur J Clin Pharmacol, 2013, 69(2): 189-195.
[4] van Hooff J, van der Walt I, Kallmeyer J, et al.Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations[J].Ther Drug Monit, 2012, 34(1): 46-52.
[5] de Widdt SN, van Schaik RHN, Soldin OP, et al.The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation[J]. Eur J Clin Pharmacol, 2011, 67(12): 1231-1241.
[6] Montini G, Ujka F, Varagnolo C, et al.The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients[J].Pediatr Nephrol, 2006, 21(5): 719-724.
[7] Zhao W, Elie V, Roussey G, et al.Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients[J].Clin Pharmacol Ther, 2009, 86(6):609-618.
[8] Woillard JB, de Winter BC, Kamar N, et al.Population pharmacokinetic model and bayesian estimator for two tacrolimus formulations-twice daily prograf and once daily advagraf[J].Br J Clin Pharmacol, 2011, 71(3): 391-402.
[9] Lapeyraque AL, Kassir N, Théorêt Y, et al.Conversion from twice- to once-daily tacrolimus in pediatric kidney recipients: a pharmacokinetic and bioequivalence study[J]. Pediatr Nephrol, 2014, 29(6): 1081-1088.
[10] Fischer L, Truneáka P, Gridelli B, et al.Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: A randomized, open-label trial[J]. Liver Transpl, 2011, 17(2): 167-177.
[11] Dirks NL, Huth B, Yates CR, et al.Pharmacokinetics of immunosuppressants: a perspective on ethnic differences[J].Int J Clin Pharmacol Ther, 2004, 42(12): 708-718.
[12] Mancinelli LM, Frassetto L, Floren LC, et al.The pharmacokine-tics and metabolic disposition of tacrolimus: a comparison across ethnic groups[J].Clin Pharmacol Ther, 2001, 69(1): 24-31.
[13] Wu P, Ni X, Wang M, et al.Polymorphisms in CYP3A5*3 and MDR1, and haplotype modulate response to plasma levels of tacrolimus in Chinese renal transplant patients[J]. Ann Transplant, 2011, 16(1): 54-60.
[14] Saint-Marcoux F, Debord J, Parant F, et al. Development and evaluation of a simulation procedure to take into account various assays for the bayesian dose adjustment of tacrolimus[J]. Ther Drug Monit, 2011, 33(2): 171-177.
[15] Kim JS, Aviles DH, Silverstein DM, et al.Effect of age,ethnicity,and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients[J].Pediatr Transplant, 2005, 9(2): 162-169.
[16] Shi Y, Li Y, Tang J, et al. Influence of CYP3A4,CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients[J].Gene, 2013, 512(2): 226-231.
[17] Zuo XC, Ng CM, Barrett JS, et al.Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokine-tic analysis[J].Pharmacogenetic Genomics, 2013, 23(5): 251-261.
[18] Cizmarikova M, Podracka L, Klimcakova L, et al.MDR1 Polymorphisms and idiopathic nephrotic syndrome in Slovak children: preliminary results[J].Med Sci Monit, 2015, 21(1): 59-68.
[19] Chen Y, Zhao Y, Wang C, et al. Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistence associated with P-glycoprotein in human leukemia K562 cells[J].Med Sci Monit, 2012, 18(10): 383-388.
[20] Stachowski J, Zanker CB, Runowski D, et al. Resistance to the-rapy in primary nephrotic syndrome: effect of MDR1 gene activity[J]. Pol Merkuriusz Lek, 2000, 8(46): 218-221.
