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Figure 6 Absolute bioavailability of a drug administered at the same dose by the intravascular (red) and extravascular (blue) route. Assuming CL to be constant and identical for the two administrations, the ratio of the AUC is 0.7, meaning that 70% of the administered dose reaches the systemic circulation intact.

5.02.5.2 Bioequivalence

The concept of bioequivalence was bom from the following observation. Digoxin, administered orally at the same dose of 1 mg but as a tablet made by two different pharmaceutical companies using different components, induced quantitatively different pharmacological effects. The two tablets were considered as being nonbioequivalent, their nonbioequivalence being a consequence of the difference in formulation between the two tablets, which released digoxin at different rates and in different amounts. Thus, one tablet could not replace the other.

The many pharmaceutical forms of the same drug that are now available, either during its development or as generics, need to be checked to see whether they will produce the same quantitative effects; in other words, that one may be substituted for another without any change in therapeutic effects. Making the likely assumption that the same plasma concentrations develop the same clinical effects, bioequivalence may be assessed by the equivalence of the relative bioavailabilities of the two pharmaceutical forms of a drug. Such equivalence is checked by comparing AUC, Cmax, and tmax, assuming that pharmacokinetic parameters remain constant during the comparison.13 These tests are carried out in healthy volunteers, using a randomized two-period, two-sequence crossover design. The statistical method for testing bioequivalence is based upon the 90% confidence interval for the ratio of the means for the parameters under consideration (test/reference). Concerning Cmax and AUC, the confidence interval is calculated using the residual of the analysis of variance (ANOVA), the data should be transformed prior to analysis using a logarithmic transformation. The analysis for tmax should be nonparametric and should be applied to untransformed data. Bioequivalence is concluded when confidence intervals are within 0.8 and 1.25 (Figure 7).

This procedure is required for any generic of a drug that has already been marketed in its original pharmaceutical form. More information about the requirements on bioavailability and bioequivalence can be found in the guidances of the European Community,18 FDA,19 and ICH.20

5.02.6 Which Pharmacokinetic Profiles for Drugs?

The overall objective of a pharmacokinetic design is to harmonize the effects of the active compounds (parent and/or active metabolites). It has to allow the drug to develop its effects under the best conditions of efficacy, intensity and duration, interindividual predictability, safety, and comfort to the patient. These requirements are obviously difficult to fulfill simultaneously, although many drugs come very close.

Specific designs are needed according to the medical use of the drug. For instance, some antibiotics are designed to target intracellular germs and must therefore be extensively distributed to tissues, whereas others are targeted to cure vascular infections. VD in the former case must be larger than in the latter. Thus, the design may be done in accordance with the specifications of the treatment. Only some general proposals in the design of pharmacokinetics are presented here based on observations of the evolution of the characteristics of recent drugs.

Figure 7 Acceptance or rejection of bioequivalence according to the confidence intervals of ratio of transformed Cmax and AUC of test and reference medicine calculated from residual of variance analysis.

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