MAD Calculations

Table 1 shows MAD calculations for several marketed drugs. An attempt was made to find literature values for solubility in the pH range of 6 to 7 to reflect conditions in the small intestine. Only one significant figure is shown for solubility, absorption rate constant, and MAD values due to the large degree of uncertainty associated with trying to assign numbers to parameters in an in vivo situation. Typical doses can also vary due to the size, age, sex, and genetics of the patient. However, inspection of Table 1 shows that for drugs that made it into the market as conventional products, namely atenolol, digoxin, furosemide, naproxen, and propranolol, the typical dose is below the MAD number that would be calculated based on the solubility of the drug at pH values expected to be found in the small intestine. For cyclosporine and griseofulvin, the dose is greater than the MAD number, and it is generally known among formulation scientists that extensive work has been carried out on the development of dosage forms to improve the absorption of cyclosporin and griseofulvin. The absorption rate constant for griseofulvin was assumed to be at the high end of the range. Even so, the MAD number is less than the dose. This demonstrates that, in some cases, only solubility needs to be measured to determine a likely problem with absorption. Both nifedipine and carbamazepine are borderline cases where the doses of the immediate-release dosage form are similar to the MAD. However, based on the commercially available dosage forms, the need for solubility-enhancing formulations to improve the bioavailability for nifedipine or carbamazepine does not appear as critical as for cyclosporine and griseofulvin. The intent of the MAD analysis summarized in Table 1 is to demonstrate that the degree of dif- ficulty in developing a commercial dosage form with regard to absorption can be estimated in a relatively straightforward manner. Inspection of Table 1 indicates that although atenolol has the lowest absorption rate constant, it has a high MAD number. Table 2 shows the predicted percent of dose absorbed for solution doses for various values for the absorption rate constant. For a drug with a low absorption rate constant like atenolol, nothing can be done to improve the percent of dose absorbed without altering the charac- teristics of the intestinal membrane. However, as long as solubility does not prevent the entire dose from dissolving, increasing the dose will continue to increase the absolute amount of drug absorbed, even while the percent of dose absorbed remains the same. While some may view incomplete absorption due to low permeability unfavorably, it does not present an obstacle to increasing absorption as long as solubility does not limit absorption.