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Past Bioavailability Problems

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 [Gibaldi, 1984]. This is an indication that more attention is now being given to formulation development during drug development. More recent example may be found by searching the FDA Enforcement Pages.

Figure 21.3.1 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 21.3.1).

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.

Other drugs with problems in the past include Acetazolamide, Aminosalicylate, Ampicillin, Aspirin, Ascorbic Acid, Chloramphenicol, Chlorothiazide, Diazepam, Furosemide, Iron, Levodopa, + 10.

Bioavailability - Bioequivalence Studies

Bioavailability studies are designed to determine either an absolute bioavailability (relative to an IV formulation) or relative bioavailability (with an alternate reference dosage form with good absorption characteristics). They can be used to compare different routes of administration, for example oral versus IV or IP versus IM.

Bioequivalence studies are designed to compare drug products. The objective is to determine if these products are bioequivalent. The dosage forms should be similar, especially the route of administration. For example, tablet versus tablet or maybe tablet versus capsule, given orally. These studies may be necessary before a generic product may be marketed. In general a relative bioavailability is determined which may be close to 100%.

Reasons for Bioequivalence Requirements

The FDA may decide to require bioavailability studies for a variety of reasons including:

Results from clinical studies indicate that different drug products produce different therapeutics results.
Results from bioavailability studies indicate that different products are not bioequivalent.
Drug has a narrow therapeutic range.
Low solubility and/or large dose.
Absorption is considerably less than 100%

References

Gibaldi, M. 1984. Biopharmaceutics and Clinical Pharmacokinetics, 3rd ed., Lea & Febiger, page 143-152.
U.S. Food and Drug Administration (FDA)
- FDA Enforcement Report Index
- FDA Recalls and Safety Alerts

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