Human dose predictions

Clearly, to be able to apply this approach in projects at an early stage, a validation is necessary that convinces the teams that this data will be useful. To this end, dose, C ax (maximum plasma concentration), and C ,i (minimum plasma concentration, at 12 h time point) data from a number of AZ CD compounds (22 compounds in total, comprising 4 acids, 6 bases, 11 neutrals, and 1 zwitterion) that have entered phase I clinical trials, usually across a number of dose levels, were collated. Human dose predictions (eD2M values) for this compound data set were also undertaken, using the models and inputs described above, while in vitro clearance was described by CLm, data determined in human hepatocytes. All clinically utilized human doses were then normalized in two ways. 

PB-PK models, sometimes referred to as biologically-based disposition models, allow for accurate extrapolation of rodent data to estimate human dose-response relationships (Paustenbach, 1995). PB-PK models, unlike compartmental models, have the capability of simulating a chemical s behavior in biological systems. The purpose of a PB-PK model is to predict the human dose-response relationship based on animal data by quantitatively estimating the delivered dose of the biologically relevant chemical species in a target tissue (Andersen etal., 1987 Clewell etal., 1994 Leung and Paustenbach, 1995 Ramsey and Andersen, 1984). 

It should be emphasized that this kind of comparison is quite theoretical, and it does not provide absolute unsafe exposures, nor does it specify safe levels. However, with the present understanding of the animal experiments it would appear prudent to lower the TLV values for the compounds for which the human exposure may be up to 1/100 of the effective human dose. Even though the extrapolation from animal tests is compounded by uncertainties, the revision of the hygienic standards concerning the pregnant worker appears justifiable in such cases. With ever-increasing female participation in the work force, more emphasis should be placed on reproductive hazards and their prediction, in the absence of adequate epidemiologic data, from experimental results. 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

There is enormous scatter in the ratio of human murine tolerable doses. Thus, while murine doses may seem to give reasonable predictions for acceptable human doses on the average, there is no predictive consistency that could be relied upon for any specific drug about to enter Phase I study. 

In the approximately 70 years since the discovery of the toxic G agents and 50 years since the subsequent development of the V agents, humans have only occassionally served as test subjects in laboratory studies designed to determine threshold toxic effects associated with low-level (nonlethal) sarin and VX vapor exposures (2-10 min) (Johns, 1952 Sim, 1956 Bramwell et al., 1963). In addition, although the toxic effects of accidental exposures and nonexperimental exposures from terrorist or military attacks are documented, critical information related to the exposure conditions can only be estimated at best. Thus, estimates of human dose-responses to nerve agent vapor exposures from such sources are often associated with significant uncertainty and are of limited utility in predicting health hazard risks. 

The remainder of this book will focus on each of the above areas. Many of these areas have been the target of research teams and have already shown potential payoffs. In 1983, Nelson (8) Identified five toxicology research needs namely 1) Improve the basis for dose and interspecies extrapolation to humans 2) predict effects... 

There are many applications of PK/PD studies in drug discovery. The prediction of human dose and regimen are important to make sure that the dose amount is developable and the dosing regimen meets the target candidate profile. In order to use preclinical PK/PD studies to predict the human dose and dose regimen, the following two issues need to be addressed (1) the exposure parameter that correlates with efficacy and (2) the human relevance of the preclinical model. 

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