Population Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors and Development of Individualized Therapy

为了比较钙调神经磷酸酶抑制剂他克莫司和环孢素的药理特性，我们检测了活体肝移植患者外周血单核细胞中钙调神经磷酸酶的活性和血药浓度。使用非线性混合效应模拟程序NONMEM进行群体药效学分析，结果表明，当环孢素浓度超过700 ng/mL时，钙调神经磷酸酶的活性几乎完全被抑制，与峰值浓度相对应。当他克莫司浓度超过20 ng/m L时，钙调神经磷酸酶的活性被部分抑制，表明他克莫司和环孢素的药理特性不同。由于两种药物对钙调神经磷酸酶的抑制显示出很大的个体差异，除了药物浓度之外，监测钙调神经磷酸酶的活性可能有助于个体化治疗。为了阐明影响他克莫司药代动力学个体间变异的因素，采用群体方法分析了P-糖蛋白(MDR1)和药物代谢酶(CYP3A4、CYP3A5)对他克莫司的影响。结果表明，肠内MDR1mRNA水平影响移植后即刻他克莫司的口腔清除，而移植肝中的CYP3A5^*3等位基因则影响术后即刻口腔清除的恢复。基于这些结果，测量每个患者的钙调神经磷酸酶活性，并考虑药物基因组学因素的药代动力学变化，将促进他克莫司精确的个体化药物治疗。

To compare the pharmacological characteristics of calcineurin inhibitors tacrolimus and cyclosporine, we measured the calcineurin activity in peripheral blood mononuclear cells as well as blood drug concentrations in living-donor liver transplant patients. Population Pharmacodynamic analysis using the nonlinear mixed-effects modeling program NONMEM showed that the calcineurin activity was almost completely inhibited over 700 ng/mL of cyclosporine which corresponded to the peak concentration. On the other hand, the calcineurin activity was partially inhibited over 20 ng/mL of tacrolimus which was the upper limit of therapeutic range, indicating that the pharmacological characteristics were different between tacrolimus and cyclosporine. Since the calcineurin inhibition by both drugs showed a large interindividual variability, the monitoring of calcineurin activity in addition to drug concentrations might be useful for individualized therapy. To clarify the factors affecting interindividual variability in tacrolimus pharmacokinetics, effects of P-glycoprotein (MDR1) and drug metabolizing enzymes (CYP3A4, CYP3A5) were analyzed by the population approach. As a result, mRNA levels of MDR1 in the intestine affected the oral clearance of tacrolimus immediately after the transplantation, while CYP3A5^*3 allele in the grafted liver influenced the recovery of oral clearance accompaning the postoperative days. Based on these results, the measurement of calcineurin activity in each patient and taking pharmacogenomic factors into consideration of pharmacokinetic changes will promote the precise individualized pharmacotherapy of tacrolimus.