M. Li, J. Venitz; Virginia Commonwealth University, Richmond, VA

BACKGROUND: The objective was to compare IV and PO routes for both MDZ and FLZ on the magnitude and time course of their metabolic DDI.
METHODS: In order to predict plasma, liver, and gut wall concentrations, semi-PBPK models for FLZ, a CYP3A inhibitor, and MDZ, a CYP3A substrate with intestinal and hepatic CYP3A metabolism, were developed - using PK parameters from clinical studies and published physiological parameters. Noncompetitive CYP3A inhibition of MDZ metabolism by FLZ was characterized with available in vitro metabolic information. The final PBPK models were validated using three clinical PK studies, in which IV/PO FLZ was co-administered with IV/PO MDZ at various intervals. Scientist 2.0 was used for modeling and simulations.
RESULTS: Model-predicted AUC0-∞ and Cmax for MDZ and FLZ were within 20% of their observed values for all three studies, confirming the validity of the PBPK model. Prospective simulations demonstrated that 400 mg FLZ - due to its long terminal t1/2 - can inhibit MDZ metabolism for up to one week. Regardless of route of administration for FLZ, the DDI magnitude (i.e., increase in MDZ AUC0-∞) after PO MDZ is almost two-fold higher than that after IV MDZ, primarily due to inhibition of pre-systemic intestinal metabolism. After IV MDZ, no IV/PO route difference is observed for FLZ. However, after PO MDZ, PO FLZ results in a 62% higher DDI than IV FLZ of the same dose - when both drugs are administered simultaneously. With increasing separation of PO MDZ from IV/PO FLZ administration, this route difference in DDI disappears within 3 hours.
CONCLUSION: There is little IV/PO route difference for FLZ with respect to its metabolic DDI on MDZ - unless it is dosed simultaneously with PO MDZ. However, MDZ is consistently more sensitive after PO than after IV administration to metabolic inhibition by FLZ.