Quantitative evaluation of the role of metabolism and transporters in drug pharmacokinetics and pharmacodynamics using PBPK modeling

Drug metabolism and membrane transporters are major determinants of the pharmacokinetic (PK), safety and efficacy profiles of drugs. Very few drugs are actually eliminated solely by direct excretion of the unchanged parent drug. In most cases the metabolic transformation of a drug is a prelude to its elimination from the body. In addition, drug transporters play an important role in all aspects of drugs ADME. Thus, any factor that modulates either or both processes is likely to alter the overall disposition of a drug. Drug metabolism and transporters contribute significantly to inter-individual differences in drug response and are also involved in drug-drug interactions, resulting in either therapeutic failure or adverse effects. In this work, we aimed to study and characterize the role of both mechanisms using in vitro, in situ, and in vivo models and generate most important parameters required for in vivo predications. Then, we quantitatively evaluated the role of metabolism and transporters in drugs PK and PD in humans using PBPK modeling.;In vitro and in vivo studies have been conducted to study the role of Niemann-Pick C1-like 1 (NPC1L1) transport protein in the nonlinear kinetics of delta-tocotrienol (delta-T3) and gamma-tocotrienol (gamma-T3). Kinetics parameters such as their oral bioavailability, V max and Km of cellular uptake, and the contribution of other uptake mechanisms have been obtained. In addition, in vitro and in situ studies have been used to study the effect of inhibition of NPC1L1 on its endogenous substrate cholesterol. The in situ studies demonstrated that intestinal perfusion of orlistat (100 microM) was able to reduce cholesterol absorption by three-fold when compared to control. Additionally, orlistat reduced the cellular uptake of cholesterol in dose dependent manner in NPC1L1 transfected cell line with an IC50=1.2 microM.;Entacapone has low and variable oral bioavailability and the underlying mechanism(s) for this behavior have not been studied. To explain such behavior and to characterize the dynamic changes in metabolism of entacapone, we first conducted in situ and in vitro studies to determine the effective permeability and transporters kinetic parameters of entacapone and its prodrug entacapone phosphate. Secondly, we developed a PBPK/PD model integrating in silico, in vitro, and in vivo PK data. The model was developed and verified in healthy volunteers and subsequently expanded to predict the PK parameters of entacapone phosphate and to assess the impact of hepatic impairment on PK of entacapone. The model showed that the extensive first-pass metabolism by UGTs in the liver and, to a lesser extent, small intestine is the reason for entacapone low bioavailability.;Indomethacin, which has been used to prevent preterm labor (PTL) during pregnancy, has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects. Thus, we developed a PBPK/PD model for indomethacin to explain the differences in indomethacin PK between pregnancy and non-pregnancy. Changes in indomethacin AUC, Cmax and Cave in pregnant women were predicted and were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted CL/Fss ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested increase in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy.;Genetic polymorphisms are major determinant of individuals' variability in drugs' efficacy and safety, which is the main challenge in current clinical practice and drug development. Hence, we developed a PBPK/PD model to predict changes in the PK parameters of two CNS medications, namely quetiapine and fluvoxamine that are substrates for polymorphic enzymes and the impact of these changes on the drugs response. Application of the PBPK models for prediction of phenotypic differences in both drugs' PK compared favorably with reported clinical data. In addition, the PBPK/PD models were able to describe the relationship between drug response and unbound fraction of drug in the brain and predict the changes in receptor/transporter occupancy percentages associated with genetic variations. Taken together, findings from the above studies showed the important role of drug metabolism and transporters in the PK and PD of drugs. In addition, our work showed the importance of PBPK modeling as a beneficial tool to predict and evaluate the role of drug metabolism and transporters on PK and PD of drugs in humans.