Utility of Minimal Physiologically-Based Pharmacokinetic (mPBPK) Models for Assessing Fractional Distribution, Oral Absorption and Series-Compartment Models of Hepatic Clearance .

Minimal physiologically-based pharmacokinetic (mPBPK) models are physiologically relevant, require less information than full PBPK models, and offer flexibility in pharmacokinetics (PK). The well-stirred hepatic model (WSM) is commonly used in PBPK, while the more plausible dispersion model (DM) poses computational complexities. The series-compartment model (SCM) mimics the DM but is easier to operate. This work implements the SCM and mPBPK models for assessing fractional tissue distribution, oral absorption and hepatic clearance using literature-reported blood and liver concentration-time data in rats for compounds mainly cleared by the liver. Further handled were various complexities including nonlinear hepatic binding and metabolism, differing absorption kinetics, and sites of administration. The SCM containing 1 to 5 ( n ) liver sub-compartments yield similar fittings and provide comparable estimates for hepatic extraction ratio ( ER ), pre-hepatic availability ( F g ), and first-order absorption rate constants ( k a ). However, they produce decreased intrinsic clearances ( CL int ) and liver-to-plasma partition coefficients ( K ph ) with increasing n as expected. Model simulations demonstrated changes in IV and oral PK profiles with alterations in K ph and k a and with hepatic metabolic zonation. The permeability (PAMPA P ) of the various compounds well explained the fitted fractional distribution ( f d ) parameters. The SCM and mPBPK models offer advantages in distinguishing systemic, extrahepatic, and hepatic clearances. The SCM allows for incorporation of liver zonation and is useful in assessing changes in internal concentration gradients potentially masked by similar blood PK profiles. Improved assessment of intra-organ drug concentrations may offer insights into active moieties driving metabolism, biliary excretion, pharmacodynamics and hepatic toxicity. Significance Statement The mPBPK and SCM models are useful in assessing oral absorption and hepatic clearance. They add flexibility in accounting for various drug- or system-specific complexities including fractional distribution, nonlinear binding and saturable hepatic metabolism, and hepatic zonation. These models can offer improved insights into the intra-organ concentrations that reflect physiologically active moieties often driving disposition, pharmacodynamics and toxicity.