S-华法林基于群体药代动力学的有限采样策略估算健康成年人的暴露量和细胞色素 P450（CYP）2C9 活性。

S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults.

机构信息

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.

出版信息

Eur J Clin Pharmacol. 2021 Sep;77(9):1349-1356. doi: 10.1007/s00228-021-03123-y. Epub 2021 Mar 23.

DOI:10.1007/s00228-021-03123-y

PMID:33754183

Abstract

PURPOSE

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.

METHODS

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%.

RESULTS

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.

CONCLUSIONS

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.

摘要

目的

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。

方法

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%。

结果

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。