Abstract：
OBJECTIVE: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes.
METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R.
RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively.
CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.
METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R.
RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively.
CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.
摘要：
目标：他克莫司，通过CYP3A4和CYP3A5酶代谢，易受药物-药物相互作用(DDI)的影响。类固醇诱导CYP3A基因增加他克莫司清除率，但效果是可变的。我们假设类固醇-他克莫司DDI的程度因CYP3A4/5基因型而异。
方法：肾移植受者（n=2462）根据功能缺失等位基因（LOF）（CYP3A5*3，*6和*7和CYP3A4*22）的数量和类固醇在移植后的前6个月中每个他克莫司低谷的使用进行分类。通过非线性混合效应模型（NONMEM）和逐步协变量模型进行群体药代动力学分析，以定义影响他克莫司清除率的重要协变量。进行了随机模拟，并将R中的mrgsolve和Shiny包装转化为Shiny应用。
结果：类固醇与适度较高（3％-11.8％）他克莫司清除率相关。接受类固醇的0-LOF等位基因患者与无类固醇相比，清除率增加最大（11.8％）。而那些有2-LOFs的患者在有类固醇的情况下的增加可以忽略不计(2.6%).在1-LOF和3/4-LOF患者中，使用类固醇可使他克莫司清除率分别增加5%和10.3%，分别。
结论：类固醇可增加他克莫司的清除率，但因CYP3A基因型而异。这在非洲血统的个体中很重要，他们更有可能不携带LOF等位基因，可能更常见的是接受类固醇治疗，需要更高的他克莫司剂量.
方法：肾移植受者（n=2462）根据功能缺失等位基因（LOF）（CYP3A5*3，*6和*7和CYP3A4*22）的数量和类固醇在移植后的前6个月中每个他克莫司低谷的使用进行分类。通过非线性混合效应模型（NONMEM）和逐步协变量模型进行群体药代动力学分析，以定义影响他克莫司清除率的重要协变量。进行了随机模拟，并将R中的mrgsolve和Shiny包装转化为Shiny应用。
结果：类固醇与适度较高（3％-11.8％）他克莫司清除率相关。接受类固醇的0-LOF等位基因患者与无类固醇相比，清除率增加最大（11.8％）。而那些有2-LOFs的患者在有类固醇的情况下的增加可以忽略不计(2.6%).在1-LOF和3/4-LOF患者中，使用类固醇可使他克莫司清除率分别增加5%和10.3%，分别。
结论：类固醇可增加他克莫司的清除率，但因CYP3A基因型而异。这在非洲血统的个体中很重要，他们更有可能不携带LOF等位基因，可能更常见的是接受类固醇治疗，需要更高的他克莫司剂量.
