PI-079 - LEVERAGING PBPK DDI APPLICATION TO ENLIGHTEN THE MECHANISMS OF THE INTERACTION BETWEEN PHENYTOIN AND OMEPRAZOLE AND POTENTIAL IMPACT IN EPILEPTIC PATIENTS.

L. Rodriguez Vera¹, X. Yin², S. Subhani³, J. Duconge⁴, V. Lukacova³, S. Schmidt², R. Cristofoletti², V. Vozmediano¹; ¹University of Florida, Gainesville, FL, USA, ²University of Florida, Orlando, FL, USA, ³Simulations Plus Inc., Lancaster, CA, USA, ⁴Universidad de Puerto Rico, San Juan, PR, USA.

Background: Physiologically-based pharmacokinetics (PBPK) has emerged as a valuable alternative for studying Drug-Drug Interactions (DDI). Phenytoin (PHT) is an antiepileptic drug and is primarily eliminated via CYP2C9 and CYP2C19 [1]. Omeprazole (OMP) is a proton pump inhibitor and its main metabolic routes are CYP2C19 and CYP3A4 [2]. We aimed to explore the mechanisms of DDI between PHT and OMP using PBPK modeling and potential impact in epileptic patients.

Methods: PBPK model development and verification (D&V) was done in GastroPlus® version 9.8.2 in a stepwise fashion: 1) PHT model D&V [3] and verification in epileptic patients, 2) OMP model D&V, 3) use of PHT and OMP models for DDI prediction and verification of DDI parameters and 4) application in clinical scenarios. PHT plasma concentrations after daily doses of 300 mg starting 2 weeks before OMP coadministration of 20, 40, and 90 mg daily/21 days were simulated. Considering the variability (2-61%) in PHT unbound fraction (fup) and its impact on the PK, the DDI impact was explored with a fup of 4.3% for simplification.

Results: Competitive inhibition and mechanism-based inactivation of CYP2C19 and CYP3A4 by OMP and its metabolites were included in the DDI model. A dose-dependent CYP2C19 inhibition by OMP on PHT and CYP2C19 and CYP3A4 on OMP itself was demonstrated. The impact of the predicted DDI was minimal with 20 mg, marginal with 40 mg and significant with 90 mg of OMP.

Conclusion: The impact of DDI mechanisms between PHT and OMP using the whole PBPK model was evaluated. The mechanisms introduced in the model support the use of OMP 20 mg daily for subjects on stable treatment with PHT 300mg daily. Further applications of this modeling work include the exploration of the impact of the DDI in different PHT fup scenarios to recommend optimal treatment regimens.

1.- Martin E, Tozer TN, Sheiner LB and Riegelman S. The clinical pharmacokinetics of Phenytoin. Journal of Pharmacokinetics and Biopharmaceutics.5(6):579-596 (1977)
2.- Shirisaka Y, Sager JE, Lutz JD, Davis C and Isoherranen N. Inhibition of CYP2C19 and CYP3A4 by Omeprazole Metabolites and their Contribution to Drug-Drug Interactions. Drug Metabolism and Disposition. 41:1414-1424(2013)
3.- Rodriguez-Vera L, Yin X, Almoslem M, Romahn K, Cicali B, Cristofoletti R and Schmidt S. Applying Physiologically-Based Pharmacokinetic (PBPK) Modeling to Assess Complex Metabolic-Mediated Drug-Drug Interactions (DDIs). American Conference on Pharmacometrics (ACoP13), poster PBPK428 (2022).