Bioavailability and Bioequivalance the Basic Approach…..

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Bioavailability:

Bioavailability is a measurement of the extent of a therapeutically active medicine that reaches the systemic circulation and is therefore available at the site of action.

For most medicines that are taken orally, the active ingredients are released in the gastrointestinal (GI) tract and arrive at their site of action via the systemic circulation.

Blood concentrations of the active ingredients and/other active metabolites thereby provide a marker for the concentration at the site of action and a valid measure of bioavailability.

A blood concentration – time curve (achieved by serial measurements over time) reflects not just the release of the active ingredient from the medicine and its absorption from the GI tract, but also other factors including pre systemic metabolism, distribution and elimination.

Bioavailability is assessed using three main pharmacokinetic variables,

  • the area under the blood drug concentration versus time curve (AUC)
  • the maximum blood concentration (Cmax)
  • the time to reach maximum concentration (Tmax)

Bioavailability example

A hypothetical drug given orally has a bioavailability of 50% (or 0.5), this is due to

  • incomplete absorption in the GI tract so that only 70% of the initial dose is absorbed.
  • subsequent metabolism of a further 20% before it reaches the systemic circulation (e.g. first pass through the liver). Therefore only 50% of the original oral dose reaches the systemic circulation.

Bioequivalence

If two medicines are bioequivalent there is no clinically significant difference in their bioavailability. Although bioequivalence is most commonly discussed in relation to generic medicines, it is important to note that bioequivalence studies are also performed for innovator

medicines in some situations such as:

  • between early and late clinical trial formulations or between the formulations used in clinical trials and the product to be marketed for new medicines
  • when changes in formulation have occurred after an innovator product has been approved, for example a change in one or more excipients (inactive ingredients)

Bioequivalence studies are a surrogate marker for clinical effectiveness and safety data as it would not normally be practical to repeat clinical studies for generic products. It is accepted that if plasma concentrations of the active ingredient of the generic and innovator medicines are the

same, then their concentration at the site of action and therefore their safety and effectiveness will be the same. In addition to being bioequivalent, a generic medicine must conform to high quality standards in terms of the method of manufacture and the purity of the final harmaceutical

form. There are internationally agreed standards for measuring and assessing bioequivalence

Acceptance Criteria for Bioequivalence:

Bioequivalence is determined based on the relative bioavailability of the innovator medicine versus the generic medicine. It is measured by comparing the ratio of the pharmacokinetic variables for the innovator versus the generic medicine where equality is 1. The acceptance criteria are such that to be classified as bioequivalent, plasma concentrations of the generic

medicine will not differ significantly compared with the innovator medicine. Studies have demonstrated that actual differences between observed mean plasma concentrations of generic and innovator medicines were no greater than 5%. In order to determine that two medicines are bioequivalent there must be no more than a 20% difference between the AUC and Cmax. This is based on international consensus that differences less than this are not clinically significant. In order to establish this, the AUC and Cmax for the generic medicine are compared to that for the innovator medicine Bioequivalence is based on a comparison of ratios where the ratio of generic to innovator for each pharmacokinetic variable does not differ by more than 8:10, this is how the range for the confidence intervals is defined:

  • 8/10 = 0.80 gives the lower limit
  • 10/8 = 1.25 gives the upper limit

The 90% confidence intervals for the ratios of both Cmax and AUC should be contained within the limits 0.80–1.25 ,Thus bioequivalence is based on ratios where the nominal equality is 1. It is not based on differences in absolute values. In practice, the generic product should have a ratio of mean values (AUC and Cmax generic: innovator) close to 1, indicating equality. If the observed ratio is closer to 0.8 or 1.25, then the data would have to contain little or no variation from the mean for the 90% confidence intervals of the ratio to lie in the 0.8 to 1.25 range that is necessary to demonstrate bioequivalence.

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