Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data
Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data
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DOI：
10.1007/s00228-013-1603-8
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发表时间：
2014-02-01
影响因子：
2.9
通讯作者：
Stahle, Lars
中科院分区：
文献类型：
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作者：
Nordmark, Anna;Andersson, Anita;Stahle, Lars
应用静态和动态（PBPK）预测模型估计AZD 2066的药物相互作用（DDI）风险。将预测结果与体内鸡尾酒研究的结果进行比较。比较了甲苯磺丁脲作为细胞色素P450 2C9（CYP 2C9）探针的各种体内测量方法，并使用人肝微粒体和CYP特异性探针底物获得了AZD 2066的体外抑制数据。DDI预测使用PBPK建模与Simplified模拟器（TM）或静态模型进行。鸡尾酒研究是一项开放标签、基线、对照相互作用研究，15名健康志愿者接受12天多次AD 2066给药。在基线和AZD 2066给药期间，同时使用100 mg咖啡因（CYP1A2探针）、500 mg甲苯磺丁脲（CYP2C9探针）、20 mg奥美拉唑（CYP2C19探针）和7.5 mg咪达唑仑（CYP3A探针）单次给药的混合药物。在不同日期给予安非他酮作为CYP2B6探针（150 mg）和100 mg美托洛尔（CYP2D6探针）。AZD 2066在体外抑制CYP1A2、CYP2B6、CYP2C9、CYP2C19和CYP2D6。静态模型预测了体内相互作用，预测的所有AUC比值> 1.1（CYP3A4除外）。PBPK模拟预测无临床相关相互作用的风险。鸡尾酒研究显示，CYP2B6和CYP2C19酶之间无相互作用，对CYP1A2、CYP2C9和CYP3A4活性可能存在弱抑制作用，对CYP2D6活性存在轻微抑制作用（29%）。甲苯磺丁脲表型指标显示CL form与AUC（TOL）、CL、Ae（met）和LnTOL（24 h）显著相关。尿液中的MRAe与CL形式无相关性。使用基于总浓度的静态方法进行DDI预测表明，AZD 20066具有潜在的抑制风险。然而，当使用基于早期人PK数据的PBPK和Simplified（TM）软件的更类似体内的动态预测方法并考虑更多参数（即血浆中的游离分数，无DDI风险）时，不能预测DDI风险。临床鸡尾酒研究显示临床相关DDI相互作用无风险或风险较低。我们的研究结果是在假设的动态预测方法预测DDI在人体内比静态模型的基础上总血浆浓度。
Static and dynamic (PBPK) prediction models were applied to estimate the drug-drug interaction (DDI) risk of AZD2066. The predictions were compared to the results of an in vivo cocktail study. Various in vivo measures for tolbutamide as a probe agent for cytochrome P450 2C9 (CYP2C9) were also compared.In vitro inhibition data for AZD2066 were obtained using human liver microsomes and CYP-specific probe substrates. DDI prediction was performed using PBPK modelling with the SimCYP simulator (TM) or static model. The cocktail study was an open label, baseline, controlled interaction study with 15 healthy volunteers receiving multiple doses of AD2066 for 12 days. A cocktail of single doses of 100 mg caffeine (CYP1A2 probe), 500 mg tolbutamide (CYP2C9 probe), 20 mg omeprazole (CYP2C19 probe) and 7.5 mg midazolam (CYP3A probe) was simultaneously applied at baseline and during the administration of AZD2066. Bupropion as a CYP2B6 probe (150 mg) and 100 mg metoprolol (CYP2D6 probe) were administered on separate days. The pharmacokinetic parameters for the probe drugs and their metabolites in plasma and urinary recovery were determined.In vitro AZD2066 inhibited CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. The static model predicted in vivo interaction with predicted AUC ratio values of > 1.1 for all CYP (except CYP3A4). The PBPK simulations predicted no risk for clinical relevant interactions. The cocktail study showed no interaction for the CYP2B6 and CYP2C19 enzymes, a possible weak inhibition of CYP1A2, CYP2C9 and CYP3A4 activities and a slight inhibition (29 %) of CYP2D6 activity. The tolbutamide phenotyping metrics indicated that there were significant correlations between CLform and AUC(TOL), CL, Ae(met) and LnTOL(24h). The MRAe in urine showed no correlation to CLform.DDI prediction using the static approach based on total concentration indicated that AZD20066 has a potential risk for inhibition. However, no DDI risk could be predicted when a more in vivo-like dynamic prediction method with the PBPK with SimCYP (TM) software based on early human PK data was used and more parameters (i.e. free fraction in plasma, no DDI risk) were taken into account. The clinical cocktail study showed no or low risks for clinical relevant DDI interactions. Our findings are in line with the hypothesis that the dynamic prediction method predicts DDI in vivo in humans better than the static model based on total plasma concentrations.