Benchmark Calculation

This provides a useful benchmark calculation that includes the key parameters that are generally recognized as limiting absorption: solubility in the GI tract and the intrinsic absorption rate constant specific to drug in solution. Other attractive features of the MAD number are that it is expressed in units of mass, facilitating communication among scientists with diverse backgrounds involved in pharmaceutical research, and the MAD number is dose-independent. This is particularly useful in early drug discovery and development because the clinical dose is unknown. The simplicity and pertinence of the MAD analysis in the drug discovery/early development phase has lead to its growing acceptance (12). The other key parameter for absorption is solubility. Given everything else the same, dissolution rate will increase with solubility. Given two drugs with the same absorption rate constant, the one with the greater solubility will have a greater MAD. In measuring solubility, using a fluid that is closer to real GI fluid rather than plain water is likely to give a more accurate prediction of the MAD. Likewise, using a dissolution media that more closely mimics GI fluid is more likely to result in a meaningful in vitro/in vivo correlation between dis- solution and absorption. TheMAD number is intended to give a “ballpark” estimate of how much drug one might expect to be absorbed if a plug of fluid with a volume expected to be found in the GI tract were to be saturated with drug, and that the drug in solution could exit the plug at a rate determined by the absorption rate constant for a period of time that the plug would typically reside in the small intestine. The typical fluid volume and GI residence time could evolve, as experience and data become available, but, for example, let them be 250 mL and three hours, respectively. In general, if the pro- jected clinical dose were below the MAD number, then drug absorption should not be a limiting factor in determining clinical efficacy. However, if the projected clinical dose were above the MAD number, limited absorption would be likely. The same could be said for projected doses for toxicological studies, and the volume and residence time could be scaled to a particular animal. The MAD number could also be used in early drug discovery to rank order candidates with regard to their ease of development. Given similar potency, a compound with a larger MAD number would have a greater dose/exposure range in which to establish safety and efficacy. Toxicity and clinical studies that show a plateau in exposure as a function of dose can be used to validate the predictive value of the MAD number.