Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France.
Clin Pharmacokinet. 2018 Nov;57(11):1459-1469. doi: 10.1007/s40262-018-0646-5.
Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients.
Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set.
A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A51, ABCB1 haplotype, PPARA42, PPARA48, and POR28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration-time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively).
The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials.
依维莫司细胞内暴露量可能优于全血谷浓度，是一个更好的疗效标志物。本研究旨在建立基于有限采样策略的依维莫司群体药代动力学模型和贝叶斯估算器，以估算肾移植受者全血和外周血单个核细胞（PBMC）中依维莫司的剂量间隔暴露量。
在相隔 4 周的 2 个不同时间点，12 例稳定的肾移植受者获得了全血和 PBMC 中依维莫司的完整浓度-时间曲线。将数据集视为 24 个个体曲线，并分为开发数据集（n = 20）和验证数据集（n = 4）。采用非参数建模法建立药代动力学模型，并在验证数据集中评估模型的表现和推导的贝叶斯估算器的表现。
建立了一个两室结构模型，采用一阶消除和两个吸收相，由两个伽马分布的和来描述。在最终模型中未保留年龄、性别、白蛋白、红细胞压积、去脂体重和 CYP3A51、ABCB1 单倍型、PPARA42、PPARA48 和 POR28 等遗传变异等测试的协变量。在给药后 0 和 1.5 h 取 2 个全血样本和 1.5 h 取 1 个 PBMC 样本的有限采样方案与梯形参考 AUC 相比，能准确估计血浆浓度-时间曲线下面积（AUC）（全血和 PBMC 浓度的相对偏差 ± 标准差分别为-3.9 ± 10.6%和 4.1 ± 12.3%）。
所建立的模型可同时准确预测全血和 PBMC 中依维莫司的暴露量，并为在前瞻性试验中探索细胞内暴露量与疗效之间的关系提供了基础。
