SUPPLEMENTARY TABLE & FIGURES

Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide

Manthena V. S. Varma,1,3 Yurong Lai,1 Emi Kimoto,1 Theunis C. Goosen,1 Ayman F. El-Kattan,1 Vikas Kumar2

1Pharmacokinetcis, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA

2Clincial Pharmacology, Pfizer Inc, Groton, Connecticut, USA

3To whom correspondance should be addressed. (e-mail: )

Figure S1 Schematic representation of repaglinide hepatic transport and metabolic input parameters used in the current model. Major effects of the inhibitory drugs considered for DDI predictions are shown.

Figure S2 Sensitivity of the uptake and metabolism parameters (SFactive, CLint,met) on the pharmacokinetic profile of repaglinide. Upper panel – Intravenous infusion (2 mg/15min); lower panel – oral dosing (0.5 mg). Modeling and simulations suggest that the observed plasma profiles can be recovered only by the change in CLint,active and the plasma exposure is relatively less sensitive to metabolic intrinsic clearance.

Figure S3 Sensitivity analysis of model input parameters on the systemic and hepatic exposure of oral repaglinide. Predicted fold change from baseline in the plasma AUC (solid line) and plasma Cmax (dotted line) and hepatic AUC (dash line) of repaglinide, following 0.25 mg oral dose, as a function of (A) Caco-2 permeability, (B) unbound fraction in enterocytes, (C) hepatic sinusoidal passive diffusion, (D) hepatic active uptake, (E) CYP3A4 intrinsic clearance, and (F) CYP2C8 intrinsic clearance. Initial values include SFactive – 16.9, fmCYP2C8 – 0.71 and CLint,met – 131 µl/min/mg.

Figure S4 A, Effect of gemfibrozil (single dose 600 mg) on the repaglinide hepatic intrinsic clearances projected by the current model. B, Effect of single gemfibrozil dose on the average intrinsic clearances (1-12h) following gemfibrozil dosing. In line with the majority of the clinical DDI studies, simulations were based on repaglinide dosing 1h after the last dose of gemfibrozil (↑); and therefore, average intrinsic clearance values between 1-12h were illustrated. Model simulations suggest that 600 mg gemfibrozil has a predominant effect on the CYP2C8, however, OATP1B1 is also inhibited up to 70%. With the current model, the CYP2C8 activity is projected to be reduced by >90% even at the subtherapeutic 100 mg dose of gemfibrozil, while the OATP1B1 activity at this dose was marginally inhibited.

3