Use of three-compartment physiologically based pharmacokinetic modeling to predict hepatic blood levels of fluvoxamine relevant for drug-drug interactions

Abstract

Using a three-compartment physiologically based pharmacokinetic (PBPK) model and a tube model for hepatic extraction kinetics, equations for calculating blood drug levels (Cb s) and hepatic blood drug levels (Chb s, proportional to actual hepatic drug levels), were derived mathematically. Assuming the actual values for total body clearance (CLtot ), oral bioavailability (F), and steady-state distribution volume (Vdss ), Cb s, and Chb s after intravenous and oral administration of fluvoxamine (strong perpetrator in drug-drug interactions, DDIs), propranolol, imipramine, and tacrine were simulated. Values for Cb s corresponded to the actual values for all tested drugs, and mean Chb and maximal Chb -to-maximal Cb ratio predicted for oral fluvoxamine administration (50 mg twice-a-day administration) were nearly 100 nM and 2.3, respectively, which would be useful for the predictions of the DDIs caused by fluvoxamine. Fluvoxamine and tacrine are known to exhibit relatively large F values despite having CLtot similar to or larger than hepatic blood flow, which may be because of the high liver uptake (almost 0.6) upon intravenous administration. The present method is thus considered to be more predictive of the Chb for perpetrators of DDIs than other methods.

Keywords: bioavailability; compartment model; distribution; drug interactions; fluvoxamine; hepatic blood level; hepatic clearance; pharmacokinetics; physiological model; simulation.