There are a number of examples of drugs products which have exhibited bioavailability problems in the past. These examples are all pre-1976 and as mentioned in the text were included in the earlier edition of the book with no further examples reported. This is an indication that more attention is now being given to formulation development during drug development.
Figure X-1, Plot of Cp versus Time
Chlorpropamide. With three products tested the peak plasma concentration after one brand was less than 1/2 the peak after the other two products (see Figure X-1).
Digoxin. The text reports a number of bioavailability problems with digoxin. One example is particularly interesting. Doctors in Israel noticed 15 cases of digoxin toxicity between Oct/Dec 1975 with almost no reports for the same period the previous year. It was found that the local manufacturer had changed the formulation to improve dissolution without telling the physicians. Urinary data suggested a two-fold increase in availability of the new formulation.
Phenytoin. Again there are a number of examples in the text. One report described an incidence of phenytoin intoxication in Australia in 1968 and 1969. Apparently the tablet diluent was changed from calcium sulfate to lactose. Later studies showed that the bioavailability was higher from the dosage form containing lactose.
The FDA may decide to require bioavailability studies for a variety of reasons including:
Copyright 2001 David W.A. Bourne