Application During Lead Optimization

In the study by Parrott et al. [7], a generic PBPK model was applied to predict plasma profiles after intravenous and oral dosing to the rat for a set of 68 compounds from six different chemical classes. The compounds were selected without particular bias and so are considered representative of current Roche discovery compounds. The physicochemical properties of the compounds are rather different from those of marketed compounds in particular they have higher lipophilicity (mean logP = 4) and lower aqueous solubility as well as a tendency to be neutral at physiological pH. The more extreme property values can present experimental determination challenges and so for consistency all predictions were made on the basis of calculated lipophilicity and protein binding while in vitro 

In a first stage, distribution was predicted with tissue composition-based equations and the estimated tissue partition coefficients were combined with clearance estimated by direct scaling of hepatocyte intrinsic clearance in a PBPK model as described earlier. 

In a second stage GastroPlus was used to simulate oral absorption, and oral profiles were produced by feeding this predicted input into a compartmental disposition model fitted to the mean observed intravenous data. 

Overall, this study indicated that generic simulation of pharmacokinetics at the lead optimization stage could be useful to predict differences in pharmacokinetic parameters of threefold or more based upon minimal measured input data. Fine discrimination of pharmacokinetics (less than twofold) should not be expected due to the uncertainty in the input data at the early stages. It is also apparent that verification of simulations with in vivo data for a few compounds of each new compound class was required to allow an assessment of the error in prediction and to identify invalid model assumptions. 

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FIGURE 8.15 An example of the change in Pareto front during a lead optimization project. At each time step, the nondominated solutions are in Bin 0. It can be seen that after Time Buckets the project ceased to produce new molecules which were true improvements over those previously discovered. In this case, the injudicious application of a potency threshold caused the optimization to stall. 

A specific type of adhesive failure is lift which is a very slow low-angle peel of a tape at its edges. The optimal physical properties to resist lift often differ from those necessary to provide high short-term peel adhesion. Longer time (low frequency) material properties become important, and the ability of the adhesive or backing to relax stress over time also becomes important, since stresses imparted to the tape during application can lead to long-term failure if they cannot be dissipated. 

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