%0 Journal Article %A Muhammad Fawad Rasool %A Ramsha Khalid %A Imran Imran %A Abdul Majeed %A Hamid Saeed %A Fawaz Fayez Alasmari %A Mohammed Mufadhe Alanazi %A Faleh Alqahtani %T Investigating the role of altered systemic albumin concentration on the disposition of theophylline in adult and pediatric asthma patients by using the physiologically based pharmacokinetic approach %D 2020 %R 10.1124/dmd.120.090969 %J Drug Metabolism and Disposition %P dmd.120.090969 %X 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 asthma patients into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma or not. 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 has adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in asthma patients. After evaluation of the developed model in the adult population, it was scaled to children on physiological basis. The model evaluation was performed by using visual predictive checks and comparison of ratio observed/predicted (Robs/Pre) for PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and disease populations as Robs/Pre for all the PK parameters were within the 2-fold error limit. The predictions in asthma patients 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 ADME in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations. %U https://dmd.aspetjournals.org/content/dmd/early/2020/05/11/dmd.120.090969.full.pdf