Maximum Absorbable Dose
The maximum absorbable dose calculation is a commonly used drug measure conceived by Kevin C. Johnson sometime around 1988 while working for Pfizer. It was used internally to characterize new drug candidates and was first reported in the article by Kevin C. Johnson and Archie C. Swindell: “Guidance in the Setting of Drug Particle Size Specification to Minimize Variability in Absorption,” Pharmaceutical Research, 13 (1996) 1795-1798. The popularity of the maximum absorbable dose was enhanced in subsequent publications by William Curatolo: “Physical chemical properties of oral drug candidates in the discovery and exploratory development settings,” Pharmaceutical Science & Technology Today, 1 (1998) 387-393 and by Christopher A. Lipinski: “Drug-like properties and the causes of poor solubility and poor permeability,” Journal of Pharmacological and Toxicological Methods, 44 (2000) 235-249.
The maximum absorbable dose has gone on to become one of the most widely used metrics for evaluating the developmental challenges facing new drug candidates.
The maximum absorbable dose (MAD) is defined as follows:
MAD = Sol × Ka × Vol × t
- Sol: drug solubility in the gastrointestinal tract (mg/mL)
- Ka: absorption rate constant (1/min)
- Vol: volume of fluid plug in the gastrointestinal tract (mL)
- t: residence tine in the gastrointestinal tract (min)
where all parameters should be determined, either experimentally or computationally, under conditions that mimic the physiology of the gastrointestinal tract.
The MAD calculation was intended as an early and approximate metric to rank drug candidates being considered for development. In addition, it was designed to give a rough approximation of how much drug could be absorbed. If the projected dose was less than the MAD, then conventional formulations should be able to deliver enough absorption to achieve therapeutic plasma concentrations. If the projected dose was greater than the MAD, then solubility-enhancing formulations might be necessary to achieve therapeutic concentrations. By design, the MAD calculation is expressed in units of mass (the same as the dose) so that it can be easily understood by a wide range of pharmaceutical scientists: clinicians, synthetic-organic chemists, project managers, toxicologists, pharmacokineticists, analytical chemists, and formulators.
In essence, the MAD calculations says that if you could keep a plug of GI fluid of a certain volume saturated with drug while it resides in the GI tract and is absorbed at a certain rate, then a certain amount of drug, MAD, could be absorbed. Obviously, there is error involved in estimating all the MAD factors, and because of propagation of error, the MAD contains a large amount of uncertainty. But when ranking drug candidates, the error in the GI fluid volume and GI residence time would presumably be the same for all candidates. Thus, the rank ordering of candidates is more reliable than assigning an absolute value to the MAD.
It was an important advance because it combined, in a conceptually simple way, four key factors that impact the extent of absorption: solubility (Cs) absorption rate constant, estimated gastrointestinal fluid volume and absorption time (T).
The MAD calculation captures the essential parameters that characterize oral absorption: solubility and the rate that drug is absorbed across the intestinal membrane. However, MAD does not consider first-pass metabolism. As a result, a drug with a favorable MAD might have low bioavailability due first-pass metabolism. Consequently, Intellipharm software does take metabolism into account as well as changing the parameters considered as constants in the MAD calculation into time-dependent variables.
When the MAD calculation was conceived, it intentionally was not associated with any particular experimental methodology. At the time, caco-2 cells were beginning to be used to determine intestinal permeability but there were questions about the lab-to-lab variability. Permeability has been used to calculate the MAD by including an intestinal surface to volume ratio. Intellipharm believes it is always prudent to validate in vitro methods for determining the absorption rate constant/permeability with pharmacokinetically determined values. Intellipharm recommends absorption rate constants determined from modeling oral solution doses crossed over with intravenous doses as a standard for validating other methods.