Bioavailability of drugs is the concentration of the drug compound that reaches the systemic circulation or the site of action.
Most of the medicines or pharmaceuticals consumed orally reach the systemic circulation through the gastrointestinal tract. These drug compounds then enter the site of action through the systemic circulation. Bioavailability of drugs is measured by assessing the active ingredient (API) concentration of the drug and any metabolites in plasma or serum. The API concentration also helps in determining the active ingredient release from the drug compounds along with its absorption, distribution, metabolism, and excretion.
The three primary variables of pharmacokinetic studies used in assessing the bioavailability of drugs are i) maximum concentration of the drug in the systemic circulation (Cmax), ii) time to reach this concentration (Tmax), and iii) time-drug concentration area under the curve (AUC).
If the bioavailability of two drug products is similar, the drug products are called bioequivalent.
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A bioequivalence study is usually carried out for generic drug product. The study evaluates clinical differences in the bioavailability of two distinct drugs. These studies are conducted to assess the efficacy of a new drug product which may have a few different excipients or inactive ingredients. Bioequivalence of drugs is evaluated to determine whether different formulations would allow the same amount of active ingredient and efficacy in the body. Bioavailability of drugs is assessed to understand what percentage of a drug gets in the systemic circulation when given through non-intravenous routes of administration (e.g., orally). These studies are essential to appraise the efficacy and quality of the new drug products.
The acceptable bioequivalence is when the 90% confidence interval of the ratio of a log-transformed exposure measure (AUC and/or Cmax) falls entirely within the range 80-125%. When the concentration of a drug compound or its metabolites in the plasma or serum is the same for two drug products, the concentration found at the site of action will also be the same. This indicates the result of the two drugs is similar due to similar concentration. Hence, the bioequivalence study demonstrates the comparable safety and efficacy of a new drug product. The purity and manufacturing process of the final product, however, still must be evaluated separately.
The pharmacokinetic method for assessing the bioavailability of drugs is an indirect method which traces the path of medication from absorption in the body until its excretion. The final assessment reveals the therapeutic index and the optimal dose of the drug. The two methods used under pharmacokinetic evaluation are plasma-level and urine-level studies. In plasma-level studies, the relation between the concentration of drug at the site of action and in the plasma is established. In urine-level studies, the urine is analyzed to assess if the drug has not been metabolized and excreted unchanged. It is necessary to analyze urinary drug levels to measure bioequivalence especially when the drug concentration in plasma or serum cannot be reliably measured.
The pharmacodynamic method is the direct way of conducting bioequivalence study which reveals the physiologic and biochemical impact of drugs on a living organism. The pharmacodynamic study uses two methods for bioequivalence evaluation, therapeutic, and acute pharmacological response. In the therapeutic assessment, we test the relationship between the clinical response when the drug concentration moves to the site of action (or reacts to the symptoms it intends to cure). In the acute pharmacological evaluation, the impact of the drug dosage and concentration on ECG, pupil diameter, EEG, etc., are tested and measured.
Generic drugs contribute to modern healthcare by accomplishing effective, safe, and low- cost alternatives to currently available modern medicines….
At the time of drug discovery, various compounds of the drugs are assessed for bioavailability. Low bioavailability can be a negative factor due to several reasons. Compound with low bioavailability may not reach therapeutic levels in systemic circulation or require very high dose which may be expensive or toxic. These compounds may require further chemical changes to improve bioavailability. These issues are evaluated during drug discovery, and the compound with good bioavailability and therapeutic value is selected for further development. We assist in the effective execution of these drug discovery studies under the supervision of our skilled scientists.
NorthEast BioLab strictly follows mandated regulations for preclinical bioavailability and bioequivalence studies, leading to secure execution and valuable data collection. At the end of preclinical investigations, the safe and efficacious drug candidates are shortlisted for further development.
Once a drug candidate moves to the clinical phase, a suitable formulation with optimum bioavailability is developed. Since the first study needs to be started with a safe dosage, tablets are prepared with only the low dose levels. As the study progresses, higher doses are administered and found safe. At this stage, it becomes necessary to reformulate the drug with higher API concentration. FDA requires that bioequivalence studies be performed to claim that these multiple tablets of smaller dose are bioequivalent to a single tablet of the higher dose.
Bioequivalence establishes generic drugs as interchangeable to the branded drug compounds with similar therapeutic and side effect profiles. Bioavailability of drugs signifies the rate and extent to which their active ingredient is absorbed systemically after dosing. NorthEast BioLab performs regulated analysis for your bioequivalence and bioavailability studies to accelerate your regulatory submission and drug approval applications such as IND, BLA, ANDA, and NDA.
Our scientists and lab analysts develop and utilize robust bioanalytical methods for evaluating the bioavailability and bioequivalence of your drugs. To illustrate, we regularly fulfill Incurred Sample Reanalysis (ISR) requirement for all our bioequivalence studies to show reliability and reproducibility of your data, as well as seek acceptance from the FDA and other regulatory agencies.
With 20+ years of experience in bioequivalence and bioavailability studies, our team at NorthEast BioLab leads the pack in benchmarking and revising internal standard operating procedures to keep pace with the dynamic regulatory environment.
Answers to additional Bioequivalence and Bioavailability Study questions popular among our potential clients.
Bioavailability (BA) refers to the fraction of an active pharmaceutical ingredient absorbed from a drug product into the systemic circulation. It is typically measured by comparing the exposure following extravascular with intravenous doses. Bioequivalence (BE) is a measure of comparability between two dosage forms of the same drug and is used to determine whether these drugs can be used interchangeably. For oral drugs, bioequivalence is determined by comparing the relative oral bioavailability of the brand name versus generic drug. Bioavailability and bioequivalence studies are performed for reformulated drugs or new generics to demonstrate comparability with marketed drug products.
The purpose of bioequivalence (BE) studies is to identify pharmaceutical equivalents or alternatives to be used interchangeably for the same therapeutic effect as a previously marketed drug. In general, we perform bioequivalence testing by comparing the bioavailability of the test product with the reference product. These days bioequivalence trials are receiving close attention because of the increased availability and utilization of generic drugs in today’s pharmaceutical market. Bioequivalent drug products must demonstrate comparability of AUC and Cmax between the two products within the bioequivalence range of typically 80-125%.
Bioavailability study is a PK study that demonstrates the rate and extent to which the active ingredient is absorbed from a drug product and becomes available to the site of action. In this context, absolute bioavailability represents the total fraction of drug absorbed by comparing the intended clinical dose route to direct IV systemic administration. On the other hand, relative bioavailability is determined by comparing the plasma concentration-time curves after administering two different formulations of the same compound by the same dosing route. Relative bioavailability is used for a direct comparison of an active pharmaceutical ingredient’s absorption between two products to determine bioequivalence. The clinical significance of bioavailability and bioequivalence is to demonstrate the comparability between reformulated or generic vs. marketed drugs.
Drug bioavailability is calculated during pharmacokinetic (PK) studies following IV and oral (or extravascular) doses. It is measured as the ratio of the dose-normalized area under the plasma time concentration curve (AUC) from the oral (or another extravascular route) administration to the AUC of an intravenous (IV) administration. In this setting, IV dosage is considered 100% available as it is administered directly into the systemic circulation. The importance of bioavailability studies lies in testing whether an active pharmaceutical ingredient can reach systemic circulation and its intended site of action while minimizing undesired off-target side effects. Typically, high bioavailability is desirable, but in some cases, low bioavailability is beneficial if the drug is administered directly to the site of action, or there are concerns about systemic toxicity.
Bioequivalence requirements from the US FDA and other agencies entail the comparability of new formulations and generics to products approved already to maintain existing standards of safety and efficacy. Bioequivalence is most often measured directly by comparing pharmacokinetic parameters following dosing (AUC and Cmax). If drug levels cannot be measured, a pharmacodynamic approach may be employed, comparing therapeutic responses and side effect profiles in patients at equivalent doses. Relative bioavailability, AUC, and Cmax are the pivotal PK parameters in a bioequivalence test study. A new product is considered bioequivalent if the relative AUC and Cmax levels following a dose are comparable to the approved product within an acceptable range, typically 80-125%, with a 90% confidence interval.
Bioequivalence studies are part of clinical research, where the systemic exposure of test and reference compounds are compared. Drug development is an expensive process with a high failure rate. Reformulated or generic drugs can be manufactured and marketed through bioequivalence study design, without the need to demonstrate therapeutic equivalence in clinical trials, given they are benchmarked against an approved product. The objective of BA/BE studies in clinical trials is to evaluate the rate and extent of absorption of a drug from a test formulation. Bioequivalence and bioavailability studies are essential in early (Pilot Bioequivalence) and late (Pivotal Bioequivalence) clinical development of drug candidates. Generally, BE studies are performed if there is a change in dose formulation, salt forms, or manufacturing process.
For filing abbreviated new drug application (ANDA), an applicant generally must demonstrate that their drug candidate is reasonably bioequivalent to the reference listed drug (RLD). To this end, FDA regulations require an applicant to use the most accurate, sensitive, and reproducible approach available among those outlined in the FDA guidance on bioequivalence (21CFR 320.24(b), Procedures for Determining Bioavailability and Bioequivalence). As per these guidelines, the descending order of determining bioequivalence (BE) includes pharmacokinetic, pharmacodynamic, clinical, and then in vitro studies. Here, the establishment of BE based on pharmacokinetics relies on endpoints such as Cmax and AUC for a direct comparison between the two products. Applicants may conduct a pilot study before full BE study to validate the analytical methodology, optimize sample collection time intervals, and flesh out protocol details.
