Physiologically Based Pharmacokinetic Modeling for Development and Applications of a Virtual Celiac Disease Population using Felodipine as a model drug

AbstractIn 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 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 utilised to verify the CeD populations. Plasma concentration-time profile and pharmacokinetic parameters were predicted and compared against 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 percent intervals captured the observed profile and variability in HV and CeD populations. Predicted and observed clearance was 56.9vs. 56.1 (L/h) in HVs. Predicted vs. observed mean ± SD AUC for extended release felodipine in different severities of CeD were values of 14.5±9.6vs. 14.4 ± 2.1, 14.6±9.0vs. 17.2 ±2.8 and 28.1±13.5vs. 25.7 ±5.0 (ng.h/ml), respectively. Accounting for physiology differences in a CeD population accurately predicte...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: ARTICLE Source Type: research