Studies on bioavailability involve investigating how and when drug substance leaves oral dosage forms to reach their site of action, often by comparison with another drug product. BE studies may also involve comparisons between two or more drug products.
A database containing 79 clinical studies on relative BE results among pediatric populations was developed and putative risk factors associated with different results were summarized.
What is Bioavailability?
Bioavailability (BA) refers to the extent to which a drug or other biological substance becomes available at its point of action. This can vary based on factors like formulation, route of administration and patient population – for instance a tablet may be absorbed differently than a solution or suspension. BA BE studies compare new formulations with existing reference products and examine whether their PK properties, such as absorption rate are similar.
Bioequivalence (BE) refers to the extent to which two pharmaceutical drug preparations provide equivalent systemic exposures when administered to their target patient population. To demonstrate BE, sponsors must conduct either one or multiple clinical trials aimed at demonstrating bioequivalence; most typically this will involve employing replicated cross-over studies conducted with healthy volunteers so as to ensure intersubject variance exceeds intrasubject variance.
At each phase of a BE study, clinical researchers are measured the concentrations of active pharmaceutical substances found in blood plasma or urine samples taken from volunteers throughout the clinical trial and compared with reference product concentrations.
BE and relative BE studies may reveal that two drug products share similar pharmacokinetic (PK) properties, such as AUC or Cmax values. When this occurs, BE limits can often be relaxed or waived altogether, especially when testing BCS class 2 drugs and solid oral dosage forms intended to be absorbed through the digestive tract. Conversely, in instances when their PK properties do not match, BE limits must either tighten further or additional bioequivalence studies conducted.
What is Bioequivalence?
Bioequivalence (BE) studies are a subcategory of drug efficacy and bioavailability studies intended to compare absorption between products marketed under their generic or other names, and their counterparts. BE studies are typically performed in volunteers – usually healthy individuals though sometimes patients – for whom blood or plasma samples are collected at regular intervals from volunteer subjects and assayed for levels of parent drug and/or its metabolite concentrations in their bodies.
Bioequivalence refers to the extent to which a drug reaches systemic circulation and becomes available at its site of action. This is typically measured using concentration-time curve analysis in healthy volunteers over two period, two sequence crossover designs. A bioequivalence claim can be made if 90% confidence interval for primary pharmacokinetic parameters (i.e. geometric mean of AUC and Cmax measurements) falls within regulatory bioequivalence limits (80% to 125%).
Pharmaceutical companies seeking BE approval must demonstrate that their product is bioequivalent to an already approved, commercially available brand-name drug. Antibody binding experiments (ABE studies) typically take place under fasted conditions; however, exceptions may allow fed studies. At BE studies, drugs are usually given out at a 1:1 ratio to participants in order to control for any non-specific factors that might interfere with drug absorption. Preferably, male and female subjects of various ages are selected so as to represent their target populations while also decreasing any potential bias from variability between subjects due to differences in drug absorption rates.
How is Bioavailability Measured?
Bioavailability refers to the proportion of drug compounds reaching their sites of action relative to total mass of drug absorbed in the body and should be an essential pharmacokinetic parameter in any drug development program.
As part of early drug development, it is crucial to measure and compare bioavailability between formulations of an active pharmaceutical ingredient (API) to understand differences among dosage forms and to identify any formulation issues which require further study or improvement. Furthermore, bioavailability comparison with existing reference products can demonstrate therapeutic equivalence.
In order to establish therapeutic equivalence, it is imperative that carefully designed comparative clinical trials meet US Food and Drug Administration (FDA) requirements. Such trials could involve well-controlled in vivo human BA/BE experiments or carefully devised in vitro dissolution tests with valid protocols.
Pharmacokinetic data obtained through BA/BE studies are used to create a regulatory compendium known as a Clinical Study Report or CSR, which details the methodology, statistical analysis, and safety evaluation of clinical trials conducted during drug development. A CSR must adhere to ICH E3 guideline which dictates its overall structure for all phases of trials in drug development.
The purpose of the ICH E3 guideline is to standardize the format, content and quality of clinical study reports for bioavailability/bioequivalence (BA/BE) and pharmacokinetic studies of pharmaceuticals. It includes sections covering general requirements, design aspects and statistical analysis methods used for BE/BA studies as well as guidance for sample size determination, power analysis and data interpretation.
How is Bioequivalence Measured?
Bioequivalence between two drug products can be measured by comparing their absorption rates and extents, with each other. When their Cmax and AUC0-t values fall within 90% confidence intervals of each other, this indicates no difference in how much active ingredient enters systemic circulation, meaning their pharmacologic effects are equivalent.
BE studies involve giving both test and reference drug products to a group of healthy volunteers randomly, who then receive either of them in turn. Serum or plasma samples are then collected at various time points to measure levels of parent drugs and their metabolites in blood before data analysis using statistical methods determine whether these two medications are bioequivalent or not.
BE studies are an integral component of generic drug development processes, as they must be approved by regulatory authorities in order to be sold as generic alternatives to innovator drugs. But BE studies must be carefully executed in order to produce results which are valid and reliable.
Ideal, test and reference products should be comparable in terms of composition and packaging; however, due to limited availability of the reference product this isn’t always possible. Therefore, to account for this fact the BE study must be performed under as similar conditions as possible to allow an accurate comparison in terms of rate and extent of absorption between both products.
Key factors influencing drug absorption include its composition, packaging, the gastrointestinal tract and individual’s physiology. If taken with food or other substances such as vitamins or physical blockades can influence drug absorption rates and extents.
What is the Difference Between Bioavailability and Bioequivalence
Bioavailability and bioequivalence (BA/BE) studies are integral parts of drug development, helping determine how quickly a substance enters systemic circulation after administration. Their results inform decisions regarding dosage adjustments, reformulations, or regulatory approval.
BA BE studies in clinical research involve administering a drug to a group of healthy human volunteers or patients and monitoring its concentration in their blood over time, depending on its formulation. This may involve oral solutions, capsules, tablets or injections depending on its nature and formulation. Once complete, results from these studies are compared against either an innovator drug product or generic equivalent to determine bioequivalence.
To demonstrate bioequivalence, test and reference drug products must possess similar pharmacokinetic properties, including similar rates of absorption, distribution, metabolism, excretion and elimination half-lives. This can typically be determined by comparing pharmacokinetic profiles following single and multiple dose administration of both drugs; furthermore bioequivalence must also be demonstrated by showing that their log-transformed exposure measures (AUC or Cmax) fall within 90% confidence limits.
To conduct a bioequivalence study, both drugs must contain active pharmaceutical ingredients (API) that can be measured using FDA-approved in vitro tests to confirm their equivalence.
Once a formulation has been proven safe and effective in clinical trials, it can be modified into higher dose levels for use as lower cost generic drugs. To do this, multiple tablets of the same drug manufactured to low dose levels are combined into a single tablet at higher API concentration before being claimed to have therapeutic equivalence with their original counterparts.