Introduction to Physiologically-Based Pharmacokinetics

Physiologically-based pharmacokinetics (PBPK) models the distribution and clearance of a drug on the basis of the drug's interactions with all the organs in a body. Because of the need for estimates or measurements of tissue:plasma partition coefficients (Kp) and tissue protein binding (fut) values, PBPK has traditionally been considered difficult to parameterize. Throughout the development and refinement of PBPK, these problems have been solved through in silico estimates of Kp and fut that were based on tissue composition of neutral lipids, phospholipids, proteins, and water ^{1 2 3 4 5 6 7 8} .

Many drug companies are now building PBPK models for all new candidate drugs early in the discovery and development cycles. These models can be parameterized using in silico (distribution) and in vitro (intrinsic clearance) methods and can provide a rough estimate of the human and animal plasma concentration versus time profiles prior to in vivo testing in animals ^{9 10} . Furthermore, these models provide one of the most successful methods for scale-up from animals to human. PBPK models also allow for an early estimate of local organ tissue concentrations which can be tied to pharmacodynamic models to get an estimate of the response in any particular tissue. The Pharmaceutical Research and Manufacturers of America (PhRMA) commissioned a study of the best methods for prediction of human exposure prior to Phase I clinical testing and published a series of papers that described the results of three years of model testing ^{11 12 13 14 15} . All previous research in this area established that PBPK was superior to allometric for interspecies extrapolation and human exposure estimation ^{16 17 18 19} .

 Based on the PhRMA initiative results, Poulin concluded that for oral administration, PBPK and mechanistic absorption simulations were inferior to allometric scaling in estimating human exposure prior to clinical testing. A careful analysis of Poulin's publication, however, indicates that in 2011, he was tasked to build his own CAT/PBPK model and used 1996 technology that resulted in the poor performance that was published in 2011. In actuality, PBPK has become a valuable tool for drug discovery ^{20 21 22} .

In a study by Cole et al. ²³ , GastroPlus® was identified as the most accurate software for predicting first-in-human exposure through in vitro to in vivo extrapolation (IVIVE). Table 2-1 and Table 2-2 compare GastroPlus® with other commercial methods and Pfizer's pre-2008 approach for estimating human exposure from in vitro and preclinical data for IV and oral profile prediction, respectively. These tables use RANK (Weighted Sum of Squares) and AFE (Average Fold Error) as metrics. The study used allometric scaling and 1-compartmental pharmacokinetics and involved data from four animal species.

Table 2-1:   Summary of IV profile prediction accuracy

Table 2-2:   Summary of oral profile prediction accuracy

The implementation of PBPK in GastroPlus® includes an internal module named PEAR Physiology™ (Population Estimates for Age-Related Physiology). This module calculates organ physiologies for American (Western), Japanese (Asian), and Chinese human models across ages ranging from premature neonates to 85 years old. Additionally, it provides adult-only organ physiologies for several commonly used pre-clinical species. See Population Estimates for Age Related Physiology.