**2.13 Characteristics to be investigated during bioequivalence studies**

Evaluation of bioavailability and bioequivalence studies will be based upon the measurement of concentrations of the active drug substances in the plasma with respective of time. In some situations, the measurements of an active or inactive metabolite may be necessary. These situations include where the concentrations of the drugs may be too low to accurately measure in the biological matrix, limitations of the analytical method, unstable drugs, and drugs with a very short halflife. Racemates should be measured by an achiral assay method. Measurement of individual enantiomers in bioequivalence studies is required where they exhibit different primary efficacy, safety activity, pharmacodynamic and pharmacokinetic characteristics with the minor enantiomer. The pharmacokinetic parameters for product are Cmax, Tmax, AUC0-t, and AUC0-∞ and for steady state are AUC0-τ, Cmax, Cmin, and degree of fluctuation should be calculated from the plasma time concentration profile.

## **2.14 Bioavailability and bioequivalence testing**

Bioavailability and bioequivalence testing are carried out for two formulations such as new and commercially marketed brand drug [25]. These studies are conducted by experimental designs such as parallel and cross over design in healthy

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

and *in vitro*-*in vivo* correlation studies.

**2.15 Criteria for bioequivalence**

the existing reference drug.

**3. Regulatory definitions**

or phenytoin for instance in the Australian market.

**3.1 Australia**

**3.2 Europe**

Australia.

**3.3 United States**

volunteer subjects but occasionally in patients. After administration of formulation under standard study conditions, plasma samples are withdrawn at regular time intervals and assayed for parent drug or occasionally metabolite concentration in plasma or urine. In some cases, concentration of drug in the blood is neither feasible nor possible to compare. Plasma concentration data are used to determine the pharmacokinetic parameters such as AUC, Cmax, Tmax, and absorption lag time (Tlag). Bioavailability studies should be conducted at different doses, especially when the drug follows nonlinear pharmacokinetics. In addition to a data from bioequivalence studies, other data may need to be submitted for evidence to meet regulatory requirements for bioequivalence includes analytical method validation

A 90% confidence interval is considered to establish bioequivalence for AUC,

The Therapeutics Goods Administration (TGA) considers two formulations to be bioequivalent if the ratios between the two formulations of Cmax and AUC should lie in the range of 0.80–1.25 and Tmax should also be similar between the two formulations [25]. There are closer limits for drugs with a narrow therapeutic index and saturable metabolism. Thus, no generic drug formulations exist in for digoxin

European Economic Area considers two formulations to be bioequivalent if they have pharmaceutically equivalency and their bioavailabilities are similar after administration in the same molar dose with respect to both efficacy and safety. For bioequivalence of two dosage forms, 90% confidence intervals are considered as

In case of FDA, two formulations are bioequivalent if the 90% confidence interval of the relative mean of Cmax, AUC0-t, and AUC0-∞ of the test or generic formulation should be within 80–125% in the fasting state. Sometimes, fed state bioequivalent comparison studies were carried out for test to reference

Tmax, and Cmax which should fall within the range of 80–125%. A 5% level of significance is taken for rejection of one sided t-test with the null hypothesis of bioequivalence. In bioavailability studies, closer limits are considered for drug that have a narrow therapeutic index, serious dose-related toxicity, steep dose, effect curve, and nonlinear pharmacokinetics within the therapeutic dose range. A wider acceptance range may be admissible if it is based on sound clinical justification. In case of suprabioavailability, a reformulation of the drug product is required and again bioequivalence study has to be carried out. Application of new formulation is required to support the clinical trial data especially for dosage recommendations. Such formulations are usually not being accepted as therapeutically equivalent to

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

*Pharmaceutical Formulation Design - Recent Practices*

Total N-1

within 20% of the reference mean.

Total 2N-1

**Table 5.**

**Table 4.**

*with n subjects.*

*with n subjects.*

**2.14 Bioavailability and bioequivalence testing**

sense that the regulatory authorities should control the consumer's risk and let the pharmaceutical company decide how much manufacturer's risk they are willing to accept. According to FDA guidelines for bioavailability studies state that "Products whose rate and extent of absorption differ by 20% or less are generally bioequivalent." The main object of bioequivalence studies is not in testing the null hypothesis of equality but to assess the difference between in two treatments groups and bioequivalence studies of two formulations is concluded that the difference is

*Design 2A comparison of ANOVA for parallel group design and 2-treatment, 2-period crossover design* 

**Sources of variance Degree of freedom (DF) Sum of squares (SS) Mean of squares (MS) F statistic** Between Treatments 1 SST2 MST2 MST2/MSE2

*Design 1 A comparison of ANOVA for parallel group design and 2-treatment, 2-period crossover design* 

**Sources of variations Sum of squares (SS) Degree of freedom (DF) Mean sum of squares (MSS) F statistic** Between treatments SST1 1 MST1 MST1/

MSE1

Subjects N-1 SSS2 MSS2 Between Period 1 SSP2 MSP2 Errors N-2 SSE2 MSE2

Error SSE1 N-2 MSE1

**2.13 Characteristics to be investigated during bioequivalence studies**

Evaluation of bioavailability and bioequivalence studies will be based upon the measurement of concentrations of the active drug substances in the plasma with respective of time. In some situations, the measurements of an active or inactive metabolite may be necessary. These situations include where the concentrations of the drugs may be too low to accurately measure in the biological matrix, limitations of the analytical method, unstable drugs, and drugs with a very short halflife. Racemates should be measured by an achiral assay method. Measurement of individual enantiomers in bioequivalence studies is required where they exhibit different primary efficacy, safety activity, pharmacodynamic and pharmacokinetic characteristics with the minor enantiomer. The pharmacokinetic parameters for product are Cmax, Tmax, AUC0-t, and AUC0-∞ and for steady state are AUC0-τ, Cmax, Cmin, and degree of fluctuation should be calculated from the plasma time concen-

Bioavailability and bioequivalence testing are carried out for two formulations such as new and commercially marketed brand drug [25]. These studies are conducted by experimental designs such as parallel and cross over design in healthy

**76**

tration profile.

volunteer subjects but occasionally in patients. After administration of formulation under standard study conditions, plasma samples are withdrawn at regular time intervals and assayed for parent drug or occasionally metabolite concentration in plasma or urine. In some cases, concentration of drug in the blood is neither feasible nor possible to compare. Plasma concentration data are used to determine the pharmacokinetic parameters such as AUC, Cmax, Tmax, and absorption lag time (Tlag). Bioavailability studies should be conducted at different doses, especially when the drug follows nonlinear pharmacokinetics. In addition to a data from bioequivalence studies, other data may need to be submitted for evidence to meet regulatory requirements for bioequivalence includes analytical method validation and *in vitro*-*in vivo* correlation studies.
