Mechanistic Physiologically Based Pharmacokinetic Research Articles

Mechanism-based prediction of particle size-dependent dissolution and absorption: Cilostazol pharmacokinetics in dogs

A previously developed physiologically based pharmacokinetic (PBPK) model for gastro-intestinal transit and absorption was combined with a mechanistic dissolution model of the Noyes–Whitney type for spherical particles with a predefined particle size distribution. To validate the combined model, the plasma concentration–time curves for cilostazol obtained in beagle dogs using three different types of suspensions with varying particle diameters were simulated. In vitro dissolution information was also available for different formulations, but this data could only predict the in vivo outcome qualitatively. The mechanistic PBPK model, on the other hand, could predict the influence of the particle size on the rate and extent of absorption under both fasted and fed conditions accurately, and the gap between the in vitro dissolution data and the in vivo outcome could successfully be explained. We conclude that by integrating the processes of particle dissolution, gastro-intestinal transit and permeation across the intestinal epithelium into a mechanistic model, oral drug absorption from suspensions can be predicted quantitatively. The model can be applied readily to typical formulation development data packages to better understand the relative importance of dissolution and permeability and pave the way for successful formulation of solid dosage forms.

Prediction of Pharmacokinetic Profile of Valsartan in Humans Based on in vitro Uptake‐Transport Data

The aim of this study was to evaluate a physiologically based pharmacokinetic (PBPK) model for predicting PK profiles in humans based on a model refined in rats and humans in vitro uptake-transport data using valsartan as a probe substrate. Valsartan is eliminated unchanged, mostly through biliary excretion, both in humans and rats. It was, therefore, chosen as model compound to predict in vivo elimination based on in vitro hepatic uptake-transport data using a fully mechanistic PBPK model. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. A mechanistic two-compartment model was used to derive the active and passive transport parameters, namely uptake Michaelis-Menten parameters (V(max) and K(m,u)) together with passive diffusion (P(dif)). These transport parameters were then used as input in a whole body physiologically based pharmacokinetic (PBPK) model. The uptake rate of valsartan was higher for rat hepatocytes (K(m,u)=28.4+/-3.7 microM, V(max)=1320+/-180 pmol/mg/min, and P(dif) =1.21+/-0.42 microl/mg/min) compared to human hepatocytes (K(m,u)=44.4+/-14.6 microM, V(max)=304+/-85 pmol/mg/min, and P(dif)=0.724+/-0.271 microl/mg/min). OATP1B1 and -1B3 parameters were correlated to human hepatocyte data, using experimentally established relative activity factors (RAF). Resulting PBPK simulations were compared for plasma- (humans and rats) and bile- (rats) concentration-time profiles following iv bolus administration of valsartan. Plasma clearances (CL(P)) for rats and humans were predicted within twofold relative to predictions based on respective in vitro data. The simulations were extended to simulate the impact of either OATP1B1 or -1B3 inhibition on plasma profile. The limited data set indicates that the mechanistic model allowed for accurate evaluation of in vitro transport data; and the resulting hepatic uptake transport kinetic parameters enabled the prediction of in vivo PK profiles and plasma clearances, using PBPK modelling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro.

Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection

The present paper proposes a modeling and simulation strategy for the prediction of pharmacokinetics (PK) of drug candidates by using currently available in silico and in vitro based prediction tools for absorption, distribution, metabolism and excretion (ADME). These methods can be used to estimate specific ADME parameters (such as rate and extent of absorption into portal vein, volume of distribution, metabolic clearance in the liver). They can also be part of a physiologically based pharmacokinetic (PBPK) model to simulate concentration–time profiles in tissues and plasma resulting from the overall PK after intravenous or oral administration. Since the ADME prediction tools are built only on commonly generated in silico and in vitro data, they can be applied already in early drug discovery, prior to any in vivo study. With the suggested methodology, the following advantages of the mechanistic PBPK modeling framework can now be utilized to explore potential clinical candidates already in drug discovery: (i) prediction of plasma (blood) and tissue PK of drug candidates prior to in vivo experiments, (ii) supporting a better mechanistic understanding of PK properties, as well as helping the development of more rationale PK-PD relationships from tissue kinetic data predicted, and hence facilitating a more rational decision during clinical candidate selection, and (iii) the extrapolation across species, routes of administration and dose levels.