Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Hematology-Oncology, University of California San Diego, San Diego, CA, USA.
Eur J Clin Pharmacol. 2021 Sep;77(9):1349-1356. doi: 10.1007/s00228-021-03123-y. Epub 2021 Mar 23.
S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults.
In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%.
S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE.
Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.
S-华法林用于表型细胞色素 P450（CYP）2C9 活性。本研究采用群体药代动力学（PK）方法评估 S-华法林有限采样策略，以估计健康成年人的 CYP2C9 活性。
在之前发表的 6 项研究中，100 名健康成年人单独或与 CYP2C9 诱导剂一起口服给予华法林 10mg 单剂量。在成年人未服用任何处方药的情况下获得 S-华法林浓度。使用非线性混合效应建模开发了群体 PK 模型。使用单点或 2 点浓度的有限采样模型（LSM）与使用来自群体 PK 模型的经验贝叶斯后验估计得出的 S-华法林 AUC 的密集采样的全 PK 曲线进行比较。LSM 选择和验证的预设标准是相关系数（R）>0.9、相对平均预测误差（%MPE）>-5 至<5%、相对平均绝对误差（%MAE）≤10%和相对均方根误差（%RMSE）≤15%。
S-华法林浓度（n=2540）用双室模型很好地描述。平均表观口服清除率为 0.56L/hr，分布容积为 35.5L。CYP2C9*3 等位基因使清除率降低 33%，洛匹那韦/利托那韦联合用药使清除率增加 42%。在 CYP2C9 组成性条件下，48 小时和 72 小时 LSM 以及 2 点 LSM 的 R、%MPE、%MAE 和%RMSE 在可接受范围内。在 CYP2C9 诱导时，S-华法林 LSM 的%MPE、%MAE 和%RMSE 不可接受。
在健康受试者中进行 S-华法林表型研究，可以使用群体 PK 方法，采用单点和/或 2 点 LSM 来估计组成型 CYP2C9 活性。
