Chapter 10

Bioavailability Studies

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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.

Chlorpropamide. Three chlorpropamide formulations were tested and the peak plasma concentration after administration of one brand was less than half the peak concentration after the other two formulations (Figure 10.3.1).

Cp versus Time after Three Chlorpropamide Formulations

Figure 10.3.1 Plot of Cp versus Time

Redrawn from Monro and Welling, 1974

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 (Gibaldi, 1984).

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:


The Biopharmaceutics Classification System (BCS)

Table 10.3.1 BCS Classification
Class Solubility Permeability
1 High High
2 Low High
3 High Low
4 Low Low

Biowaivers may be granted for drugs in Class 1 unless the drug has a narrow therapeutic range. For other drugs additional information including dissolution, perfusion and bioequivalence tests may be required.

Substitution of Generic Products

For example, levothyroxine, warfarin, phenytoin, digoxin.

Some items to consider

Item 1. Sustained or extended release products such as topical patches can be very useful products. Ideally they can deliver a continuous amount of drug over an extended period of time. This psuedo zero order delivery can provide steady drug concentrations with few problems of peak and troughs values. Unfortunately if such a product fails delivery of the total dose over a much shorter time may results in toxic concentrations.

First try simulating a typical expected result for a multiple day patch using a dose of 5,400 µg (5.4 mg) over 72 hours with kel = 0.289 hr-1 and V = 87.5 L (1.25 L/kg). (Ritschel 1992). This simulation produces concentrations of approximately 2.5 µg/L (2.5 ng/ml). (rxlist 2004). A Class I recall (FDA 2004) reported "a potential seal breach" which could "result in an increased absorption of the" drug. Repeat the simulation with a duration of 12 or 24 hours to represent a more rapid drug release. Explore the problem as a Linear Plot - Interactive graph.


References

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