摘要
目的:建立奥特康唑在中国成年健康受试者的高脂餐后群体药代动力学(popPK)模型。方法:30例成年健康受试者在高脂餐后分别单次口服150、450、600 mg奥特康唑,采用液相色谱-串联质谱法(LC-MS/MS)测定血药浓度。使用非线性混合效应模型(NONMEM)分析奥特康唑PK特征,估算popPK参数。结果:以带有吸收迟滞的一级吸收和消除的二室模型作为结构模型,PK参数以体重(WT)异速放大形式进行校正。协变量分析发现,性别(SEX)对外周分布容积有明显影响。中央室清除率(CL_(1)/F)、中央室分布容积(V_(1)/F)、室间清除率(CL_(2)/F)、外周室分布容积(V_(2)/F)、吸收速率常数(K_(a))及迟滞时间(ALAG)的群体典型值分别为0.282×(WT/70)0.75L·h^(-1)、200×(WT/70)1.66L、22.5×(WT/70)^(0.75)L·h^(-1)、333×(WT/70)^(1.66)×(1+1.09×SEX)L、0.252 h^(-1)和0.951 h。CL_(1)/F、V_(2)/F和K_(a)的个体间变异分别为30.3%、18.8%和69.7%;个体内变异分别为30.8%、24.92 ng·mL^(-1)。结论:本研究所建立的模型稳健,较好地描述了奥特康唑在中国健康成人中的群体药代动力学特征。
Objective: To develop a population pharmacokinetic(popPK) model to characterize the disposition of oteseconazole in Chinese healthy volunteers. Methods: Thirty healthy volunteers orally administrated 150, 450 or 600 mg of oteseconazole after high fat meals, respectively. Otraconazole concentrations in plasma were measured by liquid chromatography-tandem mass spectrometry(LC-MS/MS). The popPK parameters of oteseconazole were estimated using a nonlinear mixed-effects approach with NONMEM. Results:A two-compartmental model with first-order absorption and elimination, with a lag time, was selected as the pharmacokinetic structural model. PK parameters were corrected by allometric scaling based on body weight. Sex was found to have a significant effect on peripheral volume of distribution. The typical values of final model parameters CL_(1)/F, V_(1)/F, CL_(2)/F, V_(2)/F, K_(a)and ALAG were0.282×(WT/70)0.75L·h^(-1)、200×(WT/70)1.66L、22.5×(WT/70)^(0.75)L·h^(-1)、333×(WT/70)^(1.66)×(1+1.09×SEX)L、0.252 h^(-1)and 0.951 h, respectively. Inter-individual variability were 30.3%, 18.8% and 67.9% for CL_(1)/F, CL_(2)/F and K_(a), respectively.Residual error were 30.8% and 24.92 ng·m L^(-1). Conclusion: The popPK model is robust and can describe adequately the pharmacokinetic profile of oteseconazole.
作者
赵晨阳
黄原原
樊煜欣
黄慧园
俞晶晶
蒋皓
ZHAO Chenyang;HUANG Yuanyuan;FAN Yuxin;HUANG Huiyuan;YU Jingjing;JIANG Hao(Department of Clinical Pharmacology,Jiangsu Hengrui Medicine Co.,Ltd.,Lianyungang 222000,China;Clinical Pharmacology Research Center,the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine,Kunming 650000,China)
出处
《药学与临床研究》
2023年第1期6-10,47,共6页
Pharmaceutical and Clinical Research
