PDF(Pubmed)
Abstract：
In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically-based pharmacokinetic (PBPK) population for different severities of CeD was developed. Gastrointestinal physiology parameters, such as luminal pH, transit times, morphology, P-gp, and CYP3A4 expression were included in development of the CeD population. Data on physiological difference between healthy and CeD subjects were incorporated into the model as the ratio of celiac to healthy. A PBPK model was developed and verified for felodipine extended-release tablet in healthy volunteers (HVs) and then utilized to verify the CeD populations. Plasma concentration-time profile and PK parameters were predicted and compared against those observed in both groups. Sensitivity analysis was carried out on key system parameters in CeD to understand their impact on drug exposure. For felodipine, the predicted mean concentration-time profiles and 5th and 95th percentile intervals captured the observed profile and variability in the HV and CeD populations. Predicted and observed clearance was 56.9 versus 56.1 (L/h) in HVs. Predicted versus observed mean ± SD area under the curve for extended release felodipine in different severities of CeD were values of 14.5 ± 9.6 versus 14.4 ± 2.1, 14.6 ± 9.0 versus 17.2 ± 2.8, and 28.1 ± 13.5 versus 25.7 ± 5.0 (ng.h/mL), respectively. Accounting for physiology differences in a CeD population accurately predicted the PK of felodipine. The developed CeD population can be applied for determining the drug concentration of CYP3A substrates in the gut as well as for systemic levels, and for application in drug-drug interaction studies.
摘要：
在乳糜泻（CeD）中，胃肠道CYP3A4的丰度和形态受到疾病严重程度的影响。因此,暴露于CYP3A4底物和药物相互作用的程度发生改变。开发了不同程度的CeD的PBPK种群。胃肠道生理参数，如内腔pH值，运输时间,形态学,P-gp和CYP3A4表达包括在CeD群体的发育中。将健康受试者和CeD受试者之间的生理差异的数据作为乳糜泻与健康受试者的比率并入模型中。开发了PBPK模型，并在健康志愿者（HV）中验证了非洛地平缓释片，然后用于验证CeD人群。预测血浆浓度-时间曲线和药代动力学参数，并将其与两组的观察结果进行比较。对CeD中的关键系统参数进行了敏感性分析，以了解其对药物暴露的影响。对于非洛地平，预测的平均浓度-时间曲线以及第5%和第95%的间隔捕获了HV和CeD人群中观察到的曲线和变异性。预测和观察到的清除率为56.9vs.56.1（升/小时）在HV。预测vs.在不同程度的CeD中，缓释非洛地平的观察平均值±SDAUC为14.5±9.6。14.4±2.1，14.6±9.0vs.17.2±2.8和28.1±13.5vs.25.7±5.0（ng。h/ml),分别。考虑CeD人群的生理差异，可以准确预测非洛地平的PK。开发的CeD群体可用于确定肠道中CYP3A底物的药物浓度以及全身水平，以及在药物相互作用研究中的应用。
