Vertical allometry: fact or fiction?

In pharmacokinetics, vertical allometry is referred to the clearance of a drug when the predicted human clearance is substantially higher than the observed human clearance. Vertical allometry was initially reported for diazepam based on a 33-fold higher human predicted clearance than the observed human clearance. In recent years, it has been found that many other drugs besides diazepam, can be classified as drugs which exhibit vertical allometry. Over the years, many questions regarding vertical allometry have been raised. For example, (1) How to define and identify the vertical allometry? (2) How much difference should be between predicted and observed human clearance values before a drug could be declared 'a drug which follows vertical allometry'? (3) If somehow one can identify vertical allometry from animal data, how this information can be used for reasonably accurate prediction of clearance in humans? This report attempts to answer the aforementioned questions. The concept of vertical allometry at this time remains complex and obscure but with more extensive works one can have better understanding of 'vertical allometry'.