PDF(Pubmed)
Abstract：
BACKGROUND: Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability.
OBJECTIVE: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability.
METHODS: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately.
RESULTS: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3).
CONCLUSIONS: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at \"Deutsches Register Klinischer Studien\" under registration no. DRKS00017760.
OBJECTIVE: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability.
METHODS: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately.
RESULTS: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3).
CONCLUSIONS: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at \"Deutsches Register Klinischer Studien\" under registration no. DRKS00017760.
摘要：
背景：Noscapine是一种常用的止咳药，随着对其抗炎和抗肿瘤特性的持续研究。该药物具有明显的药代动力学变异性。
目的：本评估旨在使用半机械性群体药代动力学模型描述诺斯卡品的药代动力学，并确定可以解释个体间药代动力学变异性的协变量。
方法：48名健康志愿者（30名男性和18名女性，平均年龄33岁)参加了一项随机研究，两期,两阶段,两种不同液体制剂中诺可辛的交叉生物等效性研究。通过非房室分析和群体药代动力学模型分别评估了口服50mg诺斯卡辛后的诺斯卡辛血浆浓度。
结果：与参考配方相比，测试制剂的峰值血浆浓度和血浆浓度-时间曲线下面积的比率（置信区间为94.12%）为0.784（0.662-0.929）和0.827（0.762-0.925），分别。当比较CYP2C9基因型预测的表型之间的峰值血浆浓度和血浆浓度-时间曲线下面积时，均观察到p值的显着差异（<0.01）。具有零阶吸收和一阶消除过程的三隔室模型最好地描述了等离子体数据。肝室的引入能够描述noscapine的深刻首过效应。总体重和CYP2C9基因型预测的表型都被确定为明显清除的显著协变量，对于广泛代谢者（CYP2C9*1/*1和*1/*9），估计为958±548L/h，活动评分为1.5（CYP2C9*1/*2）的中间代谢者531±304L/h，活性评分为1.0（CYP2C9*1/*3，*2/*3和*3/*3）的不良代谢者和中等代谢者为343±197L/h。
结论：目前的工作有望促进noscapine未来的药代动力学/药效学发展。这项研究是在注册编号为“DeutschesRegisterKlinischerStudien”开始之前注册的。DRKS00017760。
目的：本评估旨在使用半机械性群体药代动力学模型描述诺斯卡品的药代动力学，并确定可以解释个体间药代动力学变异性的协变量。
方法：48名健康志愿者（30名男性和18名女性，平均年龄33岁)参加了一项随机研究，两期,两阶段,两种不同液体制剂中诺可辛的交叉生物等效性研究。通过非房室分析和群体药代动力学模型分别评估了口服50mg诺斯卡辛后的诺斯卡辛血浆浓度。
结果：与参考配方相比，测试制剂的峰值血浆浓度和血浆浓度-时间曲线下面积的比率（置信区间为94.12%）为0.784（0.662-0.929）和0.827（0.762-0.925），分别。当比较CYP2C9基因型预测的表型之间的峰值血浆浓度和血浆浓度-时间曲线下面积时，均观察到p值的显着差异（<0.01）。具有零阶吸收和一阶消除过程的三隔室模型最好地描述了等离子体数据。肝室的引入能够描述noscapine的深刻首过效应。总体重和CYP2C9基因型预测的表型都被确定为明显清除的显著协变量，对于广泛代谢者（CYP2C9*1/*1和*1/*9），估计为958±548L/h，活动评分为1.5（CYP2C9*1/*2）的中间代谢者531±304L/h，活性评分为1.0（CYP2C9*1/*3，*2/*3和*3/*3）的不良代谢者和中等代谢者为343±197L/h。
结论：目前的工作有望促进noscapine未来的药代动力学/药效学发展。这项研究是在注册编号为“DeutschesRegisterKlinischerStudien”开始之前注册的。DRKS00017760。
