Physiologically based pharmacokinetics (PBPK)

Abstract

Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

“…PBPK models are used to predict the time-course of a chemical in the blood or specific organs (i.e., the internal dose) affected by the agent (34). These computer-enabled models take into account key anatomical, physiological and biochemical features of laboratory animals and humans, as well as physicochemical properties of the compound of interest.…”

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

“…Mice were anesthetized with 50 to 100 mg/kg sodium pentobarbitone 5 to 10 min prior to blood collection. Blood was harvested from groups of mice (n ϭ 5) by cardiac puncture at 10,15,20,30,45,60,75, and 90 min; 2, 2.5, 3,4,5,8,12,18,24,30,36,48, and 56 h; and 3, 4, 5, and 7 days into 1-ml lithium heparin tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) and centrifuged at 3,000 ϫ g for 10 min, and the plasma was separated and stored at Ϫ80°C until analyzed by high-performance liquid chromatography (HPLC) for CQ and DCQ measurement (31). A peripheral blood film was prepared from each mouse prior to CQ dosing and at the time of euthanasia to confirm that the parasitemia data in the pharmacokinetic study mice were consistent with the pharmacodynamic study (data not shown).…”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…These models allow quantitative assessment of the relation between neuro-PK and TO. As already discussed, PBPK modeling is particularly useful in translating the obtained information from animals to humans by using the available knowledge on species-dependent physiological characteristics such as blood flow and organ volumes [53][54][55].…”