(30b) Application of Physiologically Based Pharmacokinetic Model for Drug Development

Physiologically-based pharmacokinetics (PBPK) modeling has become well-accepted in pharmaceutical research for in silico prediction of in vivo pharmacokinetics of new drugs with small to intermediate molecular size. This is a science-based, mechanistic approach that accounts for tissue size, perfusion rates, and partitioning of unbound drug into physically relevant compartments. GastroPlus^TM(Simulation Plus, Inc.) is a software tool that simulates the rate and extent of drug absorption coupled with pharmacokinetics and pharmacodynamics. The application of its advanced compartmental absorption and transit (ACAT) model with its PBPK module (PBPKPlus^TM) can provide great insight into how a drug distributes in the body, which can help to guide decisions in drug development. PBPK modeling is also a useful method for interspecies scaling and early prediction of human pharmacokinetics. This presentation will show a PBPK model that was developed for terbinafine in rats based on literature data using GastroPlus^TM v7.5, which successfully predicted human plasma concentration-time profile based only on inter-species and in vitro/in vivo extrapolation (IVIVE). Human clearance was estimated by allometric scaling using the familiar ¾-power law.

This presentation will also discuss the feasibility of applying PBPK modeling for therapeutic macromolecules. Macromolecules pose challenges for PBPK modeling due to their size, hydrolytic instability and physico-chemical properties. The lymphatic system plays an important role in the absorption and disposition of macromolecules after extravascular administration due to permeability limitations through blood capillaries. Binding between macromolecules and specific proteins also affects drug transport and clearance. Potential improvements to current PBPK models to simulate the pharmacokinetics of macromolecules will be discussed.