Definitions
Bioavailability [Shargel and Yu, 1985] indicates a measurement of the rate and extent (amount) of therapeutically active drug which reaches the general circulation.
Pharmaceutical Equivalent [Federal Register 1977] means drug products that contain identical amounts of the identical active drug ingredient, i.e., the salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and where applicable, content uniformity, disintegration times and/or dissolution rate. Pharmaceutical Alternatives [Federal Register 1977] means drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
Therapeutic Equivalents Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.
Bioequivalent Drug Products [Federal Register 1977] means pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may be equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on chronic use, or are considered medically insignificant for the particular drug product studied == Therapeutic Equivalents.
Bioequivalence Requirement [Federal Register 1977] means a requirement imposed by the Food and Drug Administration for the in vitro and/or in vivo testing of specified drug products which must be satisfied as a condition of marketing.
Brand Name [Shargel and Yu, 1985] is the trade name of the drug.
Chemical Name [Shargel and Yu, 1985] is the name used by the organic chemist to indicate the chemical structure of the drug.
Drug Product [Federal Register 1977] means a finished dosage form, e.g., tablet, capsule, or solution, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients.
Generic Name [Shargel and Yu, 1985] is the established, non proprietary or common name of the active drug in a drug product.
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%
Bioavailability study characteristics
With recently introduced products properly conducted bioavailability studies will have been performed before the product is allowed to be marketed. However products which were approved some time ago may not have been tested as thoroughly. It is therefore helpful to be able to evaluate the testing which may have been undertaken. There are a number of situations where a pharmacist is required to evaluate bioavailability study testing. When selecting drug products for a prescription, product performance should be a most important criteria. Once it is established that two or more products are equivalent, then the choice of brand can be made on the basis of economic factors, cost etc.
The evaluation of a drug product bioavailability study involves the consideration of various factors. Drug
The drug substance in each product must be the same. Bioavailability studies are conducted to compare two or more products containing the same chemical substance. We can't compare different chemical substances. The apparent volume of distribution and kel can be quite different for different drug substances, thus no interpretation of the results is possible. The first rule of bioavailability testing is that you compare the drug products with the same drug in each dosage from.
The only time that this rule is relaxed is in the case of pro-drug administration. A pro-drug is a compound which will form the drug of interest in the body. In this case it may be appropriate to compare the delivery of a dosage form containing the drug with another dosage form containing a pro-drug. This testing is generally conducted to evaluate the usefulness of the pro-drug, rather than a strict comparison of the drug products. Once the usefulness of the pro-drug is demonstrated comparisons between dosage forms all containing the pro-drug should be undertaken to evaluate the drug product performance. Drug product
Figure 21.4.1 Plot of Cp versus Time after IV and IM Administration. NOTE: AUC are the same
Usually the comparison is made between two (or more) similar products, containing exactly the same chemical substance. However, different dosage forms can be compared (when they contain the same drug). For example we could compare an IM dosage form with an IV one. By calculating the AUC values we can determine the absolute bioavailability of the IM dosage form. In this case it appears to be close to 100%. The rate of absorption for the IM dose can be determined also, but of course no comparison is possible.
Figure 21.4.2 Plot of Cp versus Time for A and B with B having Slower Absorption
Alternately we could compare brand A tablet with brand B tablet or capsule. By comparing the AUC values and ka values we can make comparisons concerning both the extent and rate of absorption. In this case A appears to be faster than B but the extent of absorption doesn't appear to be all that different.
Subjects
A number of factor are of concern; health, age, weight, enzyme status, number. Studies with humans must be carefully evaluated and approved by an Institutional Review Board (IRB). There must be an optimal risk/benefit ratio and given that in most bioavailability studies (with healthy volunteers) there is little direct benefit to the individual any risks should be minimal. All subjects must give informed consent, that includes a requirement that they be provided with clear descriptions of their risks and benefit to participation.
Health
Usually a study is designed so that each subject takes each product in turn. Thus the effect of the individual subject can be eliminated or reduced. Such a study design is called a cross- over design. Even though each subject will act as their own control it is usually best to have subjects of similar kinetic characteristic so that major variations are not introduced. Thus healthy volunteers are often preferred by drug product evaluation studies. Informed consent should be obtained from each volunteer and some biochemical and medical examination will be used to confirm their medical state. For some drugs there may be special disease states which may cause the exclusion of some volunteers. For example, in one study we looked at propranolol products, and otherwise healthy volunteers with a past history of asthma were excluded from this study.
Age
As you will see later, age can have a significant effect on drug pharmacokinetics. Elderly patients and young children can have quite different kinetics compared with young adults. In the interest of a better matched group, subjects between the ages of 18 to 35 years are preferred. Kinetic changes usually aren't important until age greater than 60.
Weight
The apparent volume of distribution is usually proportional to weight in subjects of normal weight for height. However, in overweight (or underweight) subjects the V in L/kg maybe somewhat different. Again to better match the subjects, normal weights are preferred.
Enzyme status
Smokers or subjects taking certain other drugs may have altered kinetics for the drug of interest. This can be caused by alteration of enzyme activity or by drug-drug interactions. These effects add complications to a study and an attempt is usually made to minimize these factors.
Number
The number of subjects included in the study should be sufficient to see any real (maybe 20% variation) differences in bioavailability. Usually 10 - 20 subjects are used in these studies. In clinical studies where the end-point is some clinical response, much larger numbers are required because of the greater variability in clinical response.
Assay
The same assay method should be used for all phases of the study. It is not much use using one assay for product A samples and another assay for product B samples. This wouldn't be done in a single study, however, if you were trying to compare the results from one study with those from another, different assay methods may have been used. One assay method may pick up an interference which is not indicative of the drug concentration or the bioavailability. Also the assay method should be sensitive and specific.
Design
Usually a complete cross-over design is used. With this design each subject receives all products with a wash-out period between each dose administration.
Figure 21.4.3 Figure Showing Concentrations After Two Separate Drug Administrations
Table 21.4.1 Two Product Example
| | Week 1 | Week 2 | |
| Group 1 | A | B | |
| Group 2 | B | A | for two products |
Table 21.4.2 Three Product Example
| | Week 1 | Week 2 | Week 3 | |
Group 1 | A | B | C | |
Group 2 | B | C | A | |
Group 3 | C | A | B | |
Group 4 | A | C | B | |
Group 5 | C | B | A | |
Group 6 | B | A | C | for three products |
Data analysis
Statistics
The rate of absorption can be characterized by the ka value and also the time of peak concentration. The extent of drug absorption is characterized by the F value or the peak concentration or total AUC values. Any differences in the average values of these parameters can then be analyzed statistically to determine the significance of the differences. The 5 % confidence levels is usually used as the criteria of acceptance. The analysis of variance is a technique for separating the effect of product, subject, and sequence. The significance of each of these factors can be tested.
Table 21.4.3 Analysis of Variance Table for Three-Way Cross-Over Study
| Source of Variation | d.f. | SS | MS | F | Significance Level |
| Total | 35 | 44.6 | - | - | - |
| Subject | 11 | 28.3 | 2.58 | 10.1 | p < 0.001 |
| Week | 2 | 0.14 | 0.068 | 0.27 | n.s. |
| Treatment | 2 | 11.0 | 5.55 | 21.8 | P < 0.001 |
| Residual | 20 | 5.09 | 0.255 | - | - |
By these studies the relative bioavailability of two or more products can be determined. Hopefully with proper testing we can ensure that drug products labeled to contain equivalent chemical amounts will be bioequivalent as well.
Generate typical data from a simulated bioavailability study and analyse the data using an Analysis of Variance (ANOVA).
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