Fernández-Alarcón Beatriz, Nolberger Oscar, Vidal-Alabró Anna, Rigo-Bonnin Raul, Grinyó Josep M, Melilli Edoardo, Montero Nuria, Manonelles Anna, Coloma Ana, Favà Alex, Codina Sergi, Cruzado Josep M, Colom Helena, Lloberas Nuria
Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain.
Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
Front Pharmacol. 2024 Sep 19;15:1456565. doi: 10.3389/fphar.2024.1456565. eCollection 2024.
The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.
A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5.
A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model ( < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically ( < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5 carriers was 51% higher than that of CYP3A5 non-carriers. Age also influenced CL/F variability ( < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger.
The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5 carriers in patients aged 60 years or younger would be highest, while CYP3A5 non-carriers older than 60 years would require the lowest doses.
每日一次的他克莫司缓释制剂（ER-Tac）已证明其疗效和安全性与每日两次的速释制剂（IR-Tac）相似，但针对肾移植患者，很少有基于群体的药代动力学模型用于优化剂量。因此，本研究旨在：i）为成年肾移植患者建立ER-Tac的群体药代动力学模型；ii）识别可预测药代动力学变异性的遗传因素和随时间变化的协变量，以指导移植后早期他克莫司的剂量调整。
分析了138例肾移植患者的1067份他克莫司血药浓度。138例患者中有29例在移植后第5天进行了24小时的密集采样；同时，其余患者在移植后第5、10和15天采集血药浓度。从病历中获取他克莫司的每日剂量以及遗传和人口统计学特征。在药代动力学（PK）研究的不同日期获取生化随时间变化的协变量。使用NONMEM 7.5的非线性混合效应方法对所有浓度进行同步PK分析。
具有线性消除和延迟吸收的二室模型最能描述他克莫司的药代动力学。患者间变异性与口服血药清除率（CL/F）和中央室分布容积（Vc/F）相关。将他克莫司浓度标准化为血细胞比容值45%可显著改善模型（<0.001）。该方法优于血细胞比容-血药清除率关系的标准协变量建模。CYP3A5基因型对CL/F的影响在统计学上（<0.001）和临床上均具有显著意义。CYP3A5携带者患者的CL/F比非携带者高51%。年龄也影响CL/F变异性（<0.001）。具体而言，与60岁及以下患者估计值相比，年龄每增加一岁，CL/F下降0.0562单位。
CL/F中36%的患者间变异性可由CYP3A5基因型、年龄和血细胞比容来解释。将血细胞比容标准化为45%可解释他克莫司全血浓度的变异性，这对于在治疗药物监测期间更好地解释他克莫司全血浓度至关重要。60岁及以下的CYP3A5携带者患者的剂量需求最高；而60岁以上的CYP3A5非携带者所需剂量最低。
