PII-116 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING FOR DEVELOPMENT AND APPLICATIONS OF A VIRTUAL CELIAC DISEASE POPULATION USING FELODIPINE AS A MODEL DRUG.

F. Salem¹, A. Nimavardi², J. Mudunuru³, J. Bloomer⁴, D. Tompson¹, D. Turner², K. Taskar¹; ¹GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom, ²Certara, Sheffield, United Kingdom, ³GlaxoSmithKline, Durham, NC, USA, ⁴GlaxoSmithKline, Ware, United Kingdom.

Background: 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.

Methods: 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 a CeD PBPK model as the ratio of celiac to healthy. A PBPK model was developed and verified for felodipine using intravenous, oral solution and extended-release tablet in healthy volunteers (HVs) and then applied 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 to understand their impact in CeD and on drug exposure.

Results: 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 56.9 vs. 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±9.6 vs. 14.4 ± 2.1, 14.6±9.0 vs. 17.2±2.8 and 28.1±13.5 vs. 25.7±5.0 (ng.h/ml), respectively.

Conclusion: Accounting for physiology differences in a CeD population can predict accurately 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 systemic levels, and for application in drug-drug interaction studies.