Metabolism of caffeine in non-insulin dependent diabetic patients by physiologically based pharmacokinetic modelling

Introduction: In vitro and earlier animal studies implicated altered metabolism of caffeine as a probe for CYP1A2 enzyme activity in diabetic disease state. However clinical studies in humans reported controversial findings. This study is aimed to compare the differences in the metabolism of caffeine in Non-Insulin Dependent Diabetes Mellitus (NIDDM) patients and in healthy subjects by using Physiologically Based Pharmacokinetic (PBPK) modelling with SimCYP simulator. Methodology: A mechanistic Physiologically Based Pharmacokinetic (PBPK) model based disposition study for caffeine in healthy subjects and in diabetic patients using SimCYP simulator was performed by altering the CYP1A2 abundance as reported earlier. Prior to using the model for predictions in diabetic patients, model was validated for accuracy by comparing the model predicted and observed pharmacokinetics of caffeine from four independent clinical trials in healthy subjects. Results and conclusions: Results from the study confirmed the accuracy of the default SimCYP model for predicting caffeine pharmacokinetics in healthy Caucasian subjects. PBPK model for NIDDM patients found that Caucasian diabetic patient’s caffeine clearance is 37% higher in comparison with healthy subjects and there by reduced exposure of the drug in diabetic patients suggesting a similar fate for other CYP1A2 substrates. Simulations also suggested a clinical trial design that could be utilized to further study the real differences in caffeine disposition in diabetic patients in comparison to healthy subjects.