Uno Takaya, Wada Kyoichi, Matsuda Sachi, Terada Yuka, Oita Akira, Kawase Atsushi, Takada Mitsutaka
Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Japan.
Division of Clinical Drug Informatics, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan.
Eur J Drug Metab Pharmacokinet. 2018 Dec;43(6):665-673. doi: 10.1007/s13318-018-0478-6.
Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation.
The tacrolimus pharmacokinetic profile was obtained from 65 patients during the first 5 weeks after heart transplantation. Differences in the patients' characteristics and tacrolimus pharmacokinetic parameters between the CYP3A5 expresser (*1/*1 or *1/*3 genotypes) and non-expresser (*3/*3 genotype) groups were assessed by the Chi-square test, Student's t test, or Mann-Whitney U test.
The CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes were detected in 5, 22, and 38 patients, respectively. All patients started clotrimazole therapy approximately 1 week after starting tacrolimus. Apparent clearance and dose/weight to reach the target trough concentration (C) were significantly higher in the expresser group than in the non-expresser group (0.32 vs. 0.19 L/h/kg, p = 0.0003; 0.052 vs. 0.034 mg/kg/day, p = 0.0002); there were no significant differences in the area under the concentration-time curve from 0 to 12 h (AUC) and concentrations at any sampling time point between the two groups.
Similar concentration-time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.
他克莫司是移植后使用的主要免疫抑制剂，其个体间差异较大，涉及代谢过程中的基因多态性。细胞色素P450（CYP）3A5基因的一个常见变体CYP3A5*3会影响他克莫司的血药浓度。然而，心脏移植中移植早期他克莫司的药代动力学尚未得到充分研究。我们回顾性研究了CYP3A5基因型对心脏移植早期他克莫司药代动力学的影响。
获取了65例患者心脏移植后前5周的他克莫司药代动力学资料。通过卡方检验、学生t检验或曼-惠特尼U检验评估CYP3A5表达者（*1/1或1/*3基因型）组与非表达者（*3/*3基因型）组患者特征及他克莫司药代动力学参数的差异。
分别在5例、22例和38例患者中检测到CYP3A5 *1/*1、*1/3和3/*3基因型。所有患者在开始使用他克莫司约1周后开始使用克霉唑治疗。表达者组的表观清除率及达到目标谷浓度（C）的剂量/体重显著高于非表达者组（分别为0.32对0.19 L/h/kg，p = 0.0003；0.052对0.034 mg/kg/天，p = 0.0002）；两组间0至12小时浓度-时间曲线下面积（AUC）及任何采样时间点的浓度均无显著差异。
通过基于治疗药物监测的剂量调整，在表达者组和非表达者组中获得了相似的他克莫司浓度-时间曲线。这些结果证明了CYP3A5基因型在心脏移植后基于治疗药物监测进行他克莫司剂量优化中的重要性。
