Bioavailability (BA) and bioequivalence (BE) studies play a vital role in drug development processes for both brand name medications as well as generic versions, with numerous approaches developed to measure BA and establish BE.
Studies testing how much of a drug is absorbed into volunteers or patients after administration are carried out using randomised cross-over designs with washout periods between administrations.
In vivo
Bioavailability (BA) and bioequivalence (BE) studies are an integral component of drug development. They assess how quickly and completely a medication is absorbed by the body, helping identify any potential safety concerns with it and informing decisions regarding dosage adjustments or reformulations.
BA BE studies involve in vivo testing on humans, animals, or cell cultures and involve measuring drug concentrations over time in their blood. Studies are typically administered as part of randomized, controlled trials which include administering both test and reference products to participants at various intervals and collecting blood samples at regular intervals from participants before analyzing data to ascertain bioequivalence between both products.
To accurately measure BE, both products’ absorption rates must be comparable in order to use this evaluation process as a yardstick. Two drug products are considered equivalent when their absorption rates show no discernable difference at their therapeutic target sites following administration of an identical dose of active ingredient under similar conditions – this assumption is known as two one-sided hypothesis.
Calculating BE involves considering a variety of factors, including within-subject standard deviation and ratio between relative standard deviations of test and reference products. To ensure accurate calculations, BE measures should be log-transformed; any logarithmic adjustment must be consistent across studies as indicated in study protocols and statistical analysis plans; additionally it’s crucial that clinical trial data does not undergo double log-transformation, which could cause errors to creep into BE calculations.
BE studies are an integral component of pharmaceutical industry practice and can save companies money by bypassing costly research on new drugs. Furthermore, BE studies can ensure generic medications are safe and effective – something required by regulatory bodies like the FDA and European Medicines Agency when authorizing generic versions of existing marketed medications.
The FDA has issued guidelines for conducting in vivo BA/BE studies called 21 CFR 320. These regulations outline the definitions and requirements for in vivo studies submitted as part of an NDA or ANDA application.
In vitro
In vitro BA/BE studies are an integral component of drug development and provide essential insight into how quickly drugs reach their site of action in the body. They also offer vital insight into their effectiveness, informing decisions regarding dosage adjustments, reformulations or regulatory approval of new or generic drugs as well as potential safety concerns such as interactions or adverse reactions that arise with usage.
Bioavailability is defined as the concentration of drug compounds that reach systemic circulation or its site of action after being ingested into the digestive tract and then absorbed. Bioavailability varies between individuals depending on both drug characteristics and pharmacokinetic properties, with higher bioavailabilities reaching target organs faster. Bioavailability may also be affected by factors like route of administration or manufacturing method.
Conventional human pharmacokinetic BE in vivo testing typically utilizes a single-dose, two period, two treatment and two sequence, open label randomized crossover design with fasted healthy volunteers receiving both test and reference products; plasma profiles from these drugs are then compared in order to demonstrate BE. Unfortunately, this approach has several drawbacks including post-absorption metabolism and enterohepatic recirculation issues which hinder results.
Dissolution tests and PAMPA (pharmacokinetics, permeability, metabolism, absorption and release in plasma) methods can more accurately predict in vivo BE of drugs. Pharmaceutical laboratories worldwide rely on this combination of tests and methods, which is utilized in drug development processes worldwide and save both time and money during drug development processes. A greater understanding of when and how these methods operate will improve accuracy in their results.
Pharmaceutical science should strive to reduce BE study costs as cost can have a serious detrimental impact on patient health. This is particularly evident among older adults where one-third of medications prescribed do not receive their full course due to cost issues; leading to disease burden reduction and decrease quality of life.
Pilot
Bioavailability (BA) and bioequivalence (BE) are essential aspects of drug development and regulatory approval processes, determining how much and at what rate a medication is absorbed into the body. Therefore, they play a pivotal role in both new drug discovery and generic development efforts; indeed they form an essential part of FDA approving generics by showing their equivalentness with regard to reference products – saving costs while expediting approval times.
BA/BE studies involve giving drugs to healthy volunteers or patients and monitoring the concentration of the drug over time in their blood, then comparing this data with that of a reference product. A randomised, cross-over trial with washout periods between treatments ensures that there will be no change in blood concentration between treatments.
BA/BE studies are frequently performed on oral solid dose formulations to evaluate bioavailability. Not only can these trials assess bioavailability, but they can also highlight any discrepancies in manufacturing process or formulation; in addition, trials may provide valuable information regarding modifications to dosage, formulation or mode of administration.
Pilot BA/BE studies can be an invaluable asset to researchers, particularly those new to the field. But these preliminary analyses should focus more on assessing feasibility rather than reaching statistical significance – their objectives must be clearly laid out to prevent investigators from embarking on larger studies without sufficient data and potentially running into troublesome complications.
As part of an effort to reduce uncertainty, a novel BE analysis methodology is being proposed. This differs from traditional average bioequivalence techniques by taking into account variations between individual participants and formulations – this is done via population pharmacokinetic modeling followed by distribution comparison using confusion matrices – while at the same time taking into account variability of participants and formulations themselves. It has been tested on simulated pilot BA/BE trials; results demonstrate its robustness; being capable of highlighting both positive and unfavorable differences between test products versus reference products in BE analysis.
Pivotal
Pivotal BA/BE studies must be submitted as part of an NDA or ANDA submission, usually larger studies with more complex study designs that may include gathering more biological samples (for instance blood plasma), monitoring subject safety more intensively, as well as collecting additional clinical information like pharmacodynamic responses.
Pivotal studies require more comprehensive pharmacokinetic and bioequivalence results from pivotal formulations. PK parameters typically measure absorption, distribution, metabolism, excretion of drug compounds from the body; this analysis allows comparison of their characteristics for test formulations with reference formulations.
Most BA BE studies in clinical trials inspection assignments come directly from CDER offices that review drug applications or from complaints from members of the public. When an FDA inspector visits an assignment site for inspection, records and evidence at that clinical site will be examined by them as well as how analytic measures work during clinical phase of an assignment such as measuring drug concentration in biological samples taken during this phase.
