**1. Introduction**

Bioavailability is defined as relative amount of drug from an administered dosage which enters the systemic circulation and the rate at which the drug appears in the systemic circulation. The bioavailability studies are done by measuring the concentration of the drug in the plasma or blood after administration of drug following systemic protocol of studies and documented over time. The systemic protocol is helpful for clinical trials in the early drug development, and the data obtained are used in subsequent bioequivalence studies. Bioequivalence studies were carried out to distinguish between two pharmaceutical products containing the same active substance. One drug formulated into two different formulations if they show to be therapeutically equivalent to one another in order to be considered interchangeable.

Pharmacokinetics of drug deals with the change in drug concentration in plasma and/or its metabolites in the human or animal body with respect to time following administration of the pharmaceutical product. Bioequivalence studies are used to assess the expected *in vivo* biological equivalence of two proprietary preparations of a drug. If two pharmaceutical products are said to be bioequivalent, then they

would be expected to be the same for all intents and purposes. Bioequivalence of a drug product is achieved if its extent and rate of absorption are not statically significantly different from those of reference product when administered at the same molar dose. If the bioavailability of two formulations administered in the same molar dose is similar, then they are said to be bioequivalent [1–10]. Different test methods are available to assess equivalence, including:


Bioavailability and bioequivalence studies are required to ensure therapeutic equivalence between a pharmaceutically equivalent test drug and a generic drug or reference drug. Ensuring uniformity in standards of quality, efficacy, and safety of pharmaceutical products is the fundamental responsibility of central drugs standard control organization (CDSCO) [11]. Bioequivalence has to be considered for various products containing active ingredients marketed under different licensees are clinically equivalent and interchangeable. Submission of application for new drugs under schedule Y should be required to furnish the bioavailability and bioequivalence data, that is, mainly focus on the drug release from the pharmaceutical dosage form and subsequent absorption into the systemic circulation.

Comparative bioavailability or relative bioavailability refers to a comparison of two pharmaceutical dosage forms in terms of their relative rate and extent of absorption. In some cases, two pharmaceutical formulations exhibit markedly different bioavailability, for example, a rapidly absorbed elixir and more slowly absorbed capsule. In other cases, two different dosage formulations such as tablet and a capsule may or may not exhibit very similar bioavailability [12].

$$\text{Compractive bioavailability} = \frac{\text{AUC} \, \text{po} \times Dose}{\text{AUC} \, \text{iv} \, \text{Dosepo}}.\tag{1}$$

Absolute bioavailability refers to an active pharmaceutical ingredient reaching the systemic circulation and fraction of drug absorbed ranges from 0 to 1. If F is zero, it means no drug absorptions, and the drug is completely absorbed in the systemic circulation if F = 1. The total amount of drug reaching the systemic circulation is directly proportional to the area under curve (AUC), and fraction of drug absorbed is determined by comparing the respective AUCs of the test product and the same dose of the drug administered intravenously [13].

$$\text{Absolute bioavailability} = \frac{AUCpo}{AUCpo} \tag{2}$$

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**2.1 Study object**

formulation.

**2.2 Study design**

*Bioavailability and Bioequivalence Studies DOI: http://dx.doi.org/10.5772/intechopen.85145*

Physicochemical properties such as solubility and instability of the drug, metastable transformation, poor permeability, etc., are bioavailability problems related to the drug or drugs having similar chemical structure or formulations, where a high ratio of excipients to active ingredients exists. Drugs administered other than oral and parenteral formulations design act by systemic absorption, sustained release drug formulations design act by systemic absorption, fixed dose combination products with systemic action, nonsolution pharmaceutical products which are for nonsys-

In these cases, the bioequivalence concept is not suitable, and then comparative clinical or pharmacodynamic studies are required for proving equivalence. Bioequivalence studies are used to establish links between the early and late clinical trial formulations, formulations used in clinical trials and stability studies, clinical trial formulations and to be marketed drug products. In each comparison, the new formulation or new method of manufacture shall be the test drug, and the prior

In some formulations, bioequivalence studies are not required if bioequivalence between a test drug and a reference drug may be considered self-evident with no further requirement for documentation such as when a gas is in the form of test drug, when test drugs are to be administered parenterally such as subcutaneous, intramuscular, intravenous, etc. as aqueous solution and contain the same drug in the same concentration and the same excipients in comparable concentrations. Bioequivalence studies are not required for when the test drug is in the form of solution for oral use and contains the drug in the same dose and does not contain an excipient that is known to affect gastro-intestinal absorption of the drug; when the test drug is in the form of an ophthalmic or topical product prepared as aqueous solution and contains the same active ingredients in the same concentrations and essentially the same excipients in comparable concentrations when the test drug is in the form of powder for reconstitution as a solution and the solution meets either above second and third points, when a test drug is in the form of an inhalation or a nasal spray tested by

temic use and intended act without systemic absorption are also studied.

administered with or without the same device used for reference drug.

The object of the bioavailability study decides the study protocol. A study protocol used for estimating pharmacokinetic parameters is different from a bioequivalence study carried out for comparing the test formulation with standard

The main object of the experimental design is to minimize the experimental variables and to avoid a bias [14]. *In vivo* bioavailability study is determined by

1.The nature of the reference drug and the dosage form to be tested

2.Benefit risk ratio considerations in regard to testing in humans

**2. Design and conduct of pharmacokinetic studies**

taking into consideration of the following points:

formulation shall be considered as the reference drug.

**1.2 When no need of bioequivalence studies**

#### **1.1 Types of studies required in bioequivalence studies**

For certain drugs, *in vivo* equivalence was done through either a bioequivalence study or a comparative clinical pharmacodynamic study. For oral immediate drug release formulations with systemic action have one or more adverse conditions like narrow therapeutic window, steep dose-response curve, nonlinear pharmacokinetics, presystemic elimination, unfavorable physicochemical properties.

### *Bioavailability and Bioequivalence Studies DOI: http://dx.doi.org/10.5772/intechopen.85145*

*Pharmaceutical Formulation Design - Recent Practices*

2.Comparative clinical trials

temic circulation.

test methods are available to assess equivalence, including:

3.Comparative pharmacodynamic studies in humans

measured in an accessible biological fluid such as plasma

would be expected to be the same for all intents and purposes. Bioequivalence of a drug product is achieved if its extent and rate of absorption are not statically significantly different from those of reference product when administered at the same molar dose. If the bioavailability of two formulations administered in the same molar dose is similar, then they are said to be bioequivalent [1–10]. Different

1.Comparative bioavailability studies, in which the active drug substance is

Bioavailability and bioequivalence studies are required to ensure therapeutic equivalence between a pharmaceutically equivalent test drug and a generic drug or reference drug. Ensuring uniformity in standards of quality, efficacy, and safety of pharmaceutical products is the fundamental responsibility of central drugs standard control organization (CDSCO) [11]. Bioequivalence has to be considered for various products containing active ingredients marketed under different licensees are clinically equivalent and interchangeable. Submission of application for new drugs under schedule Y should be required to furnish the bioavailability and bioequivalence data, that is, mainly focus on the drug release from the pharmaceutical dosage form and subsequent absorption into the sys-

Comparative bioavailability or relative bioavailability refers to a comparison of two pharmaceutical dosage forms in terms of their relative rate and extent of absorption. In some cases, two pharmaceutical formulations exhibit markedly different bioavailability, for example, a rapidly absorbed elixir and more slowly absorbed capsule. In other cases, two different dosage formulations such as tablet

Comparative bioavailability <sup>=</sup> *AUCpo* <sup>×</sup> *Doseiv* \_\_\_\_\_\_\_\_\_\_\_\_\_ *AUCiv* <sup>×</sup> *Dosepo*. (1)

Absolute bioavailability refers to an active pharmaceutical ingredient reaching the systemic circulation and fraction of drug absorbed ranges from 0 to 1. If F is zero, it means no drug absorptions, and the drug is completely absorbed in the systemic circulation if F = 1. The total amount of drug reaching the systemic circulation is directly proportional to the area under curve (AUC), and fraction of drug absorbed is determined by comparing the respective AUCs of the test product

For certain drugs, *in vivo* equivalence was done through either a bioequivalence study or a comparative clinical pharmacodynamic study. For oral immediate drug release formulations with systemic action have one or more adverse conditions like narrow therapeutic window, steep dose-response curve, nonlinear pharmacokinetics, presystemic elimination, unfavorable physicochemical properties.

\_\_\_\_\_\_

*AUCiv* (2)

and a capsule may or may not exhibit very similar bioavailability [12].

and the same dose of the drug administered intravenously [13].

Absolute bioavailability <sup>=</sup> *AUCpo*

**1.1 Types of studies required in bioequivalence studies**

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Physicochemical properties such as solubility and instability of the drug, metastable transformation, poor permeability, etc., are bioavailability problems related to the drug or drugs having similar chemical structure or formulations, where a high ratio of excipients to active ingredients exists. Drugs administered other than oral and parenteral formulations design act by systemic absorption, sustained release drug formulations design act by systemic absorption, fixed dose combination products with systemic action, nonsolution pharmaceutical products which are for nonsystemic use and intended act without systemic absorption are also studied.

In these cases, the bioequivalence concept is not suitable, and then comparative clinical or pharmacodynamic studies are required for proving equivalence. Bioequivalence studies are used to establish links between the early and late clinical trial formulations, formulations used in clinical trials and stability studies, clinical trial formulations and to be marketed drug products. In each comparison, the new formulation or new method of manufacture shall be the test drug, and the prior formulation shall be considered as the reference drug.
