Departments of Pharmacy Practice (M.F.R., R.K., A.M.) and Pharmacology (I.I.), Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan; Section of Pharmaceutics, University College of Pharmacy, Allama Iqbal Campus, University of the Punjab, Lahore, Pakistan (H.S.); and Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia (F.F.A., M.M.A., F.A.)
Departments of Pharmacy Practice (M.F.R., R.K., A.M.) and Pharmacology (I.I.), Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan; Section of Pharmaceutics, University College of Pharmacy, Allama Iqbal Campus, University of the Punjab, Lahore, Pakistan (H.S.); and Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia (F.F.A., M.M.A., F.A.).
Drug Metab Dispos. 2020 Jul;48(7):570-579. doi: 10.1124/dmd.120.090969. Epub 2020 May 11.
Theophylline is commonly used for the treatment of asthma and has a low hepatic clearance. The changes in plasma albumin concentration occurring in asthma may affect the exposure of theophylline. The aim of the presented work was to predict theophylline pharmacokinetics (PK) after incorporating the changes in plasma albumin concentration occurring in patients with asthma into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma. The PBPK model was developed following a systematic model building approach using Simcyp. The predictions were performed initially in healthy adults after intravenous and oral drug administration. Only when the developed adult PBPK model had adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in patients with asthma. After evaluation of the developed model in the adult population, it was scaled to children on physiologic basis. The model evaluation was performed by using visual predictive checks and comparison of ratio of observed and predicted (R) PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and diseased populations, as R for all the PK parameters were within the 2-fold error limit. The predictions in patients with asthma showed that there were no significant changes in PK parameters after incorporating the changes in serum albumin concentration. The mechanistic nature of the developed asthma-PBPK model can facilitate its extension to other drugs. SIGNIFICANCE STATEMENT: Exposure of a low hepatic clearance drug like theophylline may be susceptible to plasma albumin concentration changes that occur in asthma. These changes in systemic albumin concentrations can be incorporated into a physiologically based pharmacokinetic model to predict theophylline pharmacokinetics in adult and pediatric asthma populations. The presented work is focused on predicting theophylline absorption, distribution, metabolism, and elimination in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations.
茶碱通常用于治疗哮喘，其肝清除率较低。哮喘患者血浆白蛋白浓度的变化可能会影响茶碱的暴露。本研究旨在将哮喘患者血浆白蛋白浓度的变化纳入基于生理的药代动力学（PBPK）模型中，预测茶碱的药代动力学（PK），以观察这些变化是否会影响哮喘患者的全身茶碱浓度。该 PBPK 模型是使用 Simcyp 按照系统的模型构建方法开发的。最初在健康成年人中进行了静脉内和口服给药后的预测。只有当开发的成人 PBPK 模型能够充分预测健康成年人的茶碱 PK 时，才将血浆白蛋白浓度的变化纳入模型以预测哮喘患者的药物暴露。在对成人人群中的开发模型进行评估后，根据生理基础将其扩展到儿童。通过使用视觉预测检查和比较观察到的和预测的（R）PK 参数的比值以及它们的 2 倍误差范围来进行模型评估。该开发的 PBPK 模型有效地描述了健康和患病人群中的茶碱 PK，因为所有 PK 参数的 R 均在 2 倍误差范围内。对哮喘患者的预测表明，在纳入血清白蛋白浓度变化后，PK 参数没有发生显著变化。开发的哮喘 PBPK 模型的机制性质可以促进其扩展到其他药物。意义陈述：像茶碱这样低肝清除率的药物的暴露可能容易受到哮喘中发生的血浆白蛋白浓度变化的影响。这些系统白蛋白浓度的变化可以纳入 PBPK 模型中，以预测成人和儿科哮喘人群中的茶碱药代动力学。本研究的重点是预测在纳入报告的血清白蛋白浓度变化后，成人和儿科哮喘人群中茶碱的吸收、分布、代谢和消除，以观察它们对全身茶碱浓度的影响。
