|
|
|
|
|
|
|
clearance between species is directly proportional to their body weight (W) and MLP, and that animal (CL(A)) and human clearance (CL(H)) can be simply related according to Equation 9: |
|
|
|
|
|
|
|
|
CL(H) = CL(A) · [W(H) · MLP(A)]/[W(A) · MLP(H)] (9) |
|
|
|
|
|
|
|
|
Adopting this approach, it has been shown [48], using clearance values from published information on 60 different compounds, that generally good predictions, within ± 40%, can be made from rat (Figure 5), rabbit, or monkey clearance values, whereas the mouse data gave overall poor predictions, and dog data gave very poor predictions for a few compounds. In practice, using the information obtained from the intravenous administration to four rats or monkeys for a compound with a human clearance of 300 mL/min, the predicted range of values within 95% confidence limits would tend to fall between 240360 mL/min. As the volume of distribution is normally directly proportionally to body weight, together with the predicted clearance value, the half-life can be simply calculated and all kinetic parameters necessary to simulate blood levels in man after repeated dosing can be made. Of course, there are exceptions and these are often due to differences in metabolic routes. Thus, this in vivo scaling should be undertaken in conjunction with the in vitro studies to improve the prediction accuracy by not only choosing the most appropriate species to use in the intravenous kinetics studies but also to compare the two calculated clearance values from each method and so provide better confidence in the data. |
|
|
|
|
|
|
|
|
It can be envisaged that in the future using some or all of these approaches of QSAR, data bases, in vitro and in vivo scaling and metabolic routes, it may be possible to incorporate the data into cluster analysis or a neural network system [54] to achieve even better predictions. |
|
|
|
|
|
|
|
|
VI. Are All Preclinical ADME Studies Necessary? |
|
|
|
|
|
|
|
|
Although there is a perceived need to get a drug into man as soon as possible, harmonization of the timings and extent of preclinical studies has been difficult to achieve with no agreement reached on this subject at the recent ICH3 meeting [55], which could have been a useful opportunity to discuss in more detail the needs with regard to preclinical biodisposition. Unfortunately, this opportunity was missed and no more than a simple generalization was made. This omission should be put into the context that, unlike almost all other areas of drug development, no concise guidance is given for preclinical kinetics [2]. Admittedly, toxicokinetic guidelines have been agreed upon and this does provide a framework for the reevaluation of what studies are really necessary. These observations summarize a more detailed critique published elsewhere [56], which examines what preclinical studies are necessary. |
|
|
|
|
|