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