1] Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands [2] Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
CPT Pharmacometrics Syst Pharmacol. 2014 Feb 12;3(2):e100. doi: 10.1038/psp.2013.78.
Cyclosporine, everolimus, and tacrolimus are the cornerstone of immunosuppressive therapy in renal transplantation. These drugs are characterized by narrow therapeutic windows, highly variable pharmacokinetics (PK), and metabolism by CYP3A enzymes. Recently, the decreased activity allele, CYP3A422, was described as a potential predictive marker for CYP3A4 activity. This study investigated the effect of CYP3A422, CYP3A53, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus PK in renal transplant patients. CYP3A422 carriers showed a significant lower clearance for cyclosporine (-15%), and a trend was observed for everolimus (-7%) and tacrolimus (-16%). Patients carrying at least one CYP3A51 allele had 1.5-fold higher tacrolimus clearance compared with noncarriers; however, CYP3A53 appeared to be nonpredictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared with CYP3A53 or CYP3A422 alone. These data suggest that dose individualization of cyclosporine, everolimus, or tacrolimus therapy based on CYP3A4*22 is not indicated.CPT: Pharmacometrics Systems Pharmacology (2014); 3, e100; doi:10.1038/psp.2013.78; published online 12 February 2014.
环孢素、依维莫司和他克莫司是肾移植中免疫抑制治疗的基石。这些药物的特点是治疗窗狭窄、药代动力学（PK）高度可变，并且由 CYP3A 酶代谢。最近，发现活性降低的等位基因 CYP3A422 可作为 CYP3A4 活性的潜在预测标志物。本研究探讨了 CYP3A422、CYP3A53 和 CYP3A 组合基因型对肾移植患者环孢素、依维莫司和他克莫司 PK 的影响。CYP3A422 携带者的环孢素清除率显著降低（-15%），依维莫司（-7%）和他克莫司（-16%）也呈现出降低的趋势。至少携带一个 CYP3A51 等位基因的患者与非携带者相比，他克莫司清除率高 1.5 倍；然而，CYP3A53 似乎对依维莫司和环孢素没有预测作用。与 CYP3A53 或 CYP3A422 单独相比，CYP3A 组合基因型并不能显著提高清除率的预测能力。这些数据表明，基于 CYP3A4*22 对环孢素、依维莫司或他克莫司治疗进行剂量个体化并不合适。CPT：Pharmacometrics Systems Pharmacology（2014）；3，e100；doi:10.1038/psp.2013.78；在线发表于 2014 年 2 月 12 日。
