Bioequivalence

A bioequivalent drug product means the bioavailability and the clinical outcome of a Test Product and the Reference Listed Drug (Originator) are not significantly different. Bioequivalence allows cheaper generic drugs to be prescribed because the Test Product can be administered and used interchangeably with the Reference Listed Drug to treat patients.

Bioavailability

Bioavailability is the percentage of how much drug reaches the systemic circulation from a dosage form and is therefore available to interact at the target site of action. Drugs that are taken orally and intended for systemic (i.e. absorbed into the body) therapy must release and dissolve in gastrointestinal fluids. If the drug dissolves and readily passes through the gastrointestinal tract, it can be delivered to the target site of action via blood. Blood concentrations of the drug (and/or their active metabolites) thereby provide a marker for the concentration at the site of action and a valid measure of bioavailability. For most drugs, matching the bioavailability of the Test Product to the Originator acts as a surrogate for equivalent clinical efficacy.

Bioavailability is not just absorption

Bioavailability is not only a result of the drug's release and dissolution from the gut. Bioavailability is also a function of drug absorption, metabolism within the gut, distribution in the body, metabolism within the body and elimination. This becomes very important if you want to understand how to create a relationship between your in vitro dissolution data and in vivo pharmacokinetic data.

Determining bioavailability in vivo

During the development of a generic drug which is not subject to a biowaiver, bioavailability of a Test Product against the Reference Listed Drug is normally determined in vivo using crossover healthy human volunteer biostudies. ‘Crossover’ means the volunteer acts as their own control, so they take both the Test and Reference Listed Drugs. Typically, this type of biostudy involves administering either the Test Product or Reference Listed Drug under controlled prandial conditions such as with a meal (fed condition) or without a meal (fasting condition). Guidance on how a drug product should be tested with or without a meal in the biostudy is offered by some regulatory authorities.

At defined sequential time points after the administration of the Test Product or Reference Listed Drug, blood samples are taken and drug content (and possibly metabolites) is determined quantitatively. The drug blood levels are plotted against time to give a pharmacokinetic curve. From this curve various pharmacokinetic parameters are determined: extent (Area under the curve: AUC), maximum blood concentration (Cmax) and time to maximum concentration (Tmax) for the drug product. After a washout period, the volunteer then takes the other remaining dosage form in a crossover study to enable the pharmacokinetic profile of the Test Product and Reference Listed Drug to be compared statistically primarily using AUC and Cmax. To establish the Test Formulation and Reference Drug are bioequivalent there must be less than 20% difference between the two AUC’s (amount of drug absorbed) and the two Cmax's (maximum concentration reached) in the plasma.

The difference

The ratio AUC and Cmax of the Test Product (generic drug) to Reference Listed Drug for systemic exposure must not differ by more than 20% which has been selected by regulatory bodies as being not clinically significant. However, the range for the confidence intervals must fall between 0.80 for the lower limit and 1.25 for the upper limit.

Successful bioequivalence

Successful bioequivalence is achieved by matching the pharmacokinetic profiles of the Test Product with the Originator as described above. This matching of the pharmacokinetic parameters allows extrapolation of the Test Product to indications (treatments for disease) and patient groups for which the Reference Listed Drug has been previously approved.

How Biorelevant Media can help

Biorelevant dissolution can be extremely useful during development of the Test Formulation because you can make sure the drug release (and subsequent absorption and consequent bioavailability) of the Test Product in simulated gastrointestinal fluids closely matches the release profile of the Reference Listed Drug.