Application During Clinical Lead Selection

Such examples extend PBPK simulations to prediction of target effect and appear very powerful for generation of insights into the efficacy/lack of efficacy in vivo in relation to receptor occupancy. Consequently, such PBPK/PD simulations can be used as a filter between high-throughput screening and in vivo efficacy in order to prioritize compounds expected to be active in vivo. 

In a first step the scaling of intrinsic clearances determined in rat hepatocytes was compared to in vivo clearance. When taking account of non-linearity, the estimated hepatic metabolic clearance values were in reasonable agreement with observed total clearances, which ranged from 7 to 35 mL/min/kg, and it was considered reasonable to estimate the expected clearances in human by a similar scaling of human hepatocyte data. The error around the mean predicted human clearance was based on the variability seen in different batches of human hepatocytes. 

Volume of distribution predicted from tissue composition-based equations showed an average fold error of 2.2 and the correlation of predicted versus observed volume for the five compounds was poor. For the prediction of volume of distribution it was assumed that the volume in human (L/kg) was the same as the observed volume in the rat (ranging from 0.9 to 2.8 L/kg for the five compounds). Due to the uncertainty in the prediction of volume, the error range associated with this parameter was set as a uniform distribution over a twofold range. 

There was a direct relationship between the effect and the plasma concentration in the rat pharmacodynamic data and it was well described by a simple Emax model. Based on preclinical models for efficacy, a 90% effect was considered as the target for therapeutic effect. Finally the human C90 (human concentration corresponding to 90% effect, C90 man) was estimated by accounting for the different affinities and unbound fractions of each compound for the rat and human receptors as follows  

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