General Considerations

Subpart B of the Bioavailability and Bioequivalence Requirements in 21 CFR Part 320 lists the following in vivo and in vitro approaches to determining bioequivalence in descending order of accuracy, sensitivity, and reproducibility [9]:

• In vivo measurement of active moiety or moieties in blood, plasma, or serum.

• In vivo measurement of the active moiety in urine.

• In vivo pharmacologic (pharmacodynamic) comparison.

• Well-controlled clinical trials.

• In vitro comparison.

• Any other approach deemed appropriate by FDA.

Figure 1 illustrates, for a model of oral dosage form performance, why the most sensitive approach is to measure the drug in biological fluids, such as blood, plasma, or serum. The active ingredient leaves the solid dosage form and dissolves in the gastrointestinal tract, and following absorption through the gut wall, appears in the systemic circulation. The step involving dissolution of the drug substance prior to absorption is the critical step, necessary for the absorption of the drug, that is determined by the formulation. Other steps illustrated in the diagram are patient- or subject-determined processes not directly related to formulation performance. Variability of the measured endpoint increaseswitheachadditionalstepin the process. Therefore, variability of clinical measures is quite high compared to blood concentration measures. Figure 2 shows that the blood concentration of a drug directly reflects the amount of drug delivered from the dosage form.

In situations where a drug cannot be reliably measured in blood, it may be appropriate to base bioequivalence evaluation on an in vivo test in humans in which an acute pharmacologic (pharmacodynamic) effect is measured as a function of time. Generally,thepharmacodynamicresponse plotted against the logarithm of dose appears as a sigmoidal curve, as shown in Fig. 3. It is assumed that, after absorption from the site of delivery, the drug or active metabolite is delivered to the site of activity and, through binding to a receptor or some other mechanism, elicits a quantifiable pharmacodynamic response. Since additional steps contribute to the observed pharmacodynamic response, a pharmacodynamic assay is not as sensitive to drug formulation performance as blood drug concentrations. In

Pharmacokinetic Clinical/FD

Dosage Form Measurement Measurement

Performance

Pharmacokinetic Clinical/FD

Dosage Form Measurement Measurement

Performance

FIGURE 1 The most sensitive approach in evaluating bioequivalence of two formulations is to measure drug concentration in biological fluids, as illustrated in this diagram showing the relationship between dosage form performance and therapeutic response. Following oral dosing, the active ingredient leaves the solid dosage form, dissolves in the gastrointestinal tract, and, following absorption through the gut wall, appears in the systemic circulation. Formulation performance is the major factor determining the critical steps of dosage form disintegration and drug substance dissolution prior to absorption. All other steps following in vivo drug substance dissolution are patient-or subject-determined processes not directly related to formulation performance. The variability of the measured endpoint increases with each additional step in the process, such that variability of clinical measures is quite high compared to that of blood concentration measures. As a result, a pharmacodynamic or clinical approach is not as accurate, sensitive, and reproducible as an approach based on plasma concentrations.

FIGURE 1 The most sensitive approach in evaluating bioequivalence of two formulations is to measure drug concentration in biological fluids, as illustrated in this diagram showing the relationship between dosage form performance and therapeutic response. Following oral dosing, the active ingredient leaves the solid dosage form, dissolves in the gastrointestinal tract, and, following absorption through the gut wall, appears in the systemic circulation. Formulation performance is the major factor determining the critical steps of dosage form disintegration and drug substance dissolution prior to absorption. All other steps following in vivo drug substance dissolution are patient-or subject-determined processes not directly related to formulation performance. The variability of the measured endpoint increases with each additional step in the process, such that variability of clinical measures is quite high compared to that of blood concentration measures. As a result, a pharmacodynamic or clinical approach is not as accurate, sensitive, and reproducible as an approach based on plasma concentrations.

developing a pharmacodynamic assay for bioequivalence evaluation, it is critical to select the correct dose. The dose should be in the range that produces a change in response, as shown in the midportion of the curve. In other words, the pharmacodynamic assay should be sensitive to small changes in dose. A dose that is too high will produce a minimal response at the plateau phase of the dose-response curve, such that even large differences in dose will show little or no change in pharmacodynamic effect. Depending on the type of response, a pharmacodynamic study can be conducted in healthy subjects. The pharmacodynamic response selected should directly reflect dosage form performance and availability at the site of activity but may not necessarily reflect therapeutic efficacy.

FIGURE 2 The blood concentration of a drug directly reflects the amount of drug delivered from the dosage form. The corresponding responses over a wide range of doses will be of adequate sensitivity to detect differences in bioavailability between two formulations. This is illustrated for two widely different doses, D1 and D2. Any differences in dosage form performance are reflected directly by changes in blood concentration (R1 and R2).

FIGURE 2 The blood concentration of a drug directly reflects the amount of drug delivered from the dosage form. The corresponding responses over a wide range of doses will be of adequate sensitivity to detect differences in bioavailability between two formulations. This is illustrated for two widely different doses, D1 and D2. Any differences in dosage form performance are reflected directly by changes in blood concentration (R1 and R2).

If it is not possible to develop reliable bioanalytical or pharmacodynamic assays, then it may be necessary to evaluate bioequivalence in a well-controlled trial with clinical endpoints. This type of bioequivalence study is conducted in patients and is based on evaluation of a therapeutic, i.e., clinical response. The clinical response follows a similar dose-response pattern to the pharmacodynamic response, as shown in Fig. 3. Thus, in designing bioequivalence studies with clinical endpoints, the same considerations for dose selection apply as for bioequivalence studies with pharmacodynamic endpoints. As with a pharmacodynamic study, the appropriate dose for a bioequivalence study with clinical endpoints should be on the linear rising portion of the dose-response curve, since a response in this range will be the most sensitive to changes in formulation performance. Due to high variability and the sometimes subjective nature of clinical evaluations, the clinical response is often not as sensitive to differences in drug formulation performance as a pharmacodynamic response. For these

Di D2

FIGURE 3 In evaluating bioequivalence in a study with pharmacodynamic or clinical endpoints, it is critical to select a dose that falls on the middle ascending portion of the sigmoidal dose—response curve. The most appropriate dose for a study based on pharmacodynamic or clinical endpoints should be in the range that produces a change in response (R1), as shown in the midportion of the curve (D1). A dose that is too high will produce a minimal response at the plateau phase of the dose—response curve, such that even large differences in dose (D2) will show little or no change in pharmacodynamic or clinical effect (R2). Thus, two formulations which are quite different may appear to be bioequivalent.

Di D2

FIGURE 3 In evaluating bioequivalence in a study with pharmacodynamic or clinical endpoints, it is critical to select a dose that falls on the middle ascending portion of the sigmoidal dose—response curve. The most appropriate dose for a study based on pharmacodynamic or clinical endpoints should be in the range that produces a change in response (R1), as shown in the midportion of the curve (D1). A dose that is too high will produce a minimal response at the plateau phase of the dose—response curve, such that even large differences in dose (D2) will show little or no change in pharmacodynamic or clinical effect (R2). Thus, two formulations which are quite different may appear to be bioequivalent.

reasons, the clinical approach is the least accurate, sensitive, and reproducible of the in vivo approaches to determining bioequivalence.

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