No notes for slide. Bioavailability and Bioequivalence Studies 2. Morphine, OC pills 9. Fundamental Bioequivalence Assumption When a generic drug is claimed bioequivalent to a Reference drug, it is assumed that they are therapeutically equivalent Chemistry 1.
Chemistry 2. Manufacturing 2. Manufacturing 3. Controls 3. Controls 4. Labeling 4. Labeling 5. Testing 5. Testing 6. Animal Studies 7. Clinical Studies 6. Bioequivalence 8. Bioavailability Methods used to assess Equivalence I. Pharmacokinetic Studies II. Pharmacodynamic Studies III. Comparative Clinical Studies IV. Dissolution 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. 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. 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.
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. In initial study, it is acceptable to replace a subject withdrawal or dropout once it has provided the substituted subject follows the same protocol originally intended for the withdrawn subject and subject is tested under similar conditions.
The number of subjects involved in a study is determined by the following considerations: The level of significant should be 0. The error variance associated with the primary characteristics to be studied as estimated from a pilot experiment, from previous studies.
The studies should be performed on healthy adult volunteers with the aim to minimize variability between the study drugs. Subjects may be males or females; however, the choice of gender should be consistent with usage and safety criteria of the drug. To minimize intra and intersubject variation, the study design should be standardized as much as possible and acceptable.
Generally, a single dose study should be conducted after an overnight fast at least 10 hours and subsequent fasting of 4 hours after administration dosing. For multiple dose studies, 2 hours of fasting before and after the dose are acceptable. Estimation of C max and T max for the modified release products or drug is given with food in such case fed state studies also been carried out in addition to the normal fasting state bioavailability studies [ 22 ].
During fed state studies, the consumption of a high fat breakfast of — KCals is required before dosing. A single standard diet should be followed taking into consideration of all the Indian subcontinent people. The high fat breakfast must be consumed approximately 15 minutes before dosing in fed state condition.
Study conditions such as study environment, diet, fluid intake, post dosing postures, exercise, sampling schedules, etc. These conditions are stated in the protocol, and at the end of the study, these should be complied, to assure that all variability factors involved in the study to minimize the products to be tested. Least 48 hours before commencement, the study subjects abstain from smoking, drinking alcohol, xanthine containing foods, coffee, tea and beverages, and fruit juices.
Steady state study is considered in the following conditions: The drug has a long terminal elimination half-life. For drugs, which are toxic or have adverse effects that are ethically should not be administered to patients but they are a necessary part of therapy cytotoxics.
For modified release products or sustained release products which assess the fluctuation in plasma drug concentration at steady state. For combination products where the ratio of plasma concentration of the individual drugs is important. Ideally, the biological samples collected as per the sampling procedure have to be analyzed immediately after the study but most of the times the samples are stored for several days before subjected to analysis.
During storage, the drug may undergo a chemical degradation, adsorption on the walls of the container, etc. The analytical method used for the estimation of the active ingredient responsible for the therapeutic efficacy must be selective and sensitive. In the analysis of blood and urine, the major problem is to extract quantitatively and then separate the intact drug from its major metabolites or even to separate a mixture of two or more drugs from their metabolite.
Pharmacokinetic methods are used for the assessment of bioavailability of drug products that exists as a linear relation between the drug level in the biological fluid and therapeutic response. Therefore, these methods are also known indirect methods. Because therapeutically active drug can be accurately measured in biological fluids, plasma and urine data give the most objective information on bioavailability [ 23 ].
Plasma data are most widely used and accepted method for the assessment of bioavailability of the drug product. The basic assumption in this method is that drug products that are bioequivalent product super imposable plasma level time curve.
The parameters T max and C max are the measures of the rate of absorption of the drug, while the parameters AUC is a measure of the extent of absorption. Urinary excretion method is based on the general observation that the rate of urinary excretion of a drug is directly proportional to the concentration of the drug in the blood.
Therefore, the bioavailability can be calculated as the ratio of the total amount of the unchanged drug recovered in urine following the administration of test and standard formulations. Urinary metabolite excretion data are not used for the estimation of bioavailability since the drug can undergo metabolism at different sites including the gut and liver, and the rates of metabolism may vary because of various reasons.
The relative bioavailability should lie within an acceptance range of 0. In case of an especially narrow therapeutic range, the acceptance range may need to be tighter. In rare cases such as highly variable drugs, a wider acceptance range may be acceptable if it has right clinical justification. C max ratio is the measure of relative bioavailability that may be more variable than the AUC ratio, and a wider acceptance range may be acceptable. The range used in the protocol should be justified taking into account safety and efficacy consideration.
Tmax is a measure of release or action or signs for a relation to adverse effects. The two pharmacodynamic methods used for the estimation of bioavailability are based on the measurement of acute pharmacological effect and clinical response. In order to estimate the bioavailability of a drug product accurately by measurement of acute pharmacological effect, the following criteria should meet.
These are an easily measurable response such as heart rate, ECG, blood pressure, pupil diameter, etc. Due to biological and experimental variations, some differences always exist, and it is necessary to ascertain whether these differences are simply chance occurrences or are due to actual differences in treatment administered to the subjects.
Statistical methods are used to evaluate the pharmacokinetic data in order to identify the different sources of variation and if possible to measure the contribution of each identified variable and isolate the specific observation of primary interest. The analysis of variance ANOVA , a statistical procedure that used for a crossover design is widely used method in bioavilability testing [ 24 ]. The pharmacokinetic parameters derived from blood drug concentration and time from bioavailability studies are subjected to ANOVA.
Bioavailability studies are designed in two ways, and these are design 1 and design 2. Design 1 is parallel design in which the subjects divide into two treatment groups and assign one treatment to each group.
Design 2 is crossover design in which each subject has one block and applies both the treatments to each subject with washout period in between them. In a parallel design, variability due to the treatment is considered, and in the crossover design, variability due to treatment, subject, and period are considered to minimize variability.
The error mean sum of square for design 1 MSE1 will be greater than the error mean sum of square for design 2 MSE2 if the degrees of freedom for SSE are the same in the both designs then error variability is greater in the parallel group design compared to the crossover design Tables 3 and 4. The treatment mean sum of squares is larger than the error mean sum of squares if difference is achieved between the treatments.
Then the chances of getting treatment mean sum of squares being bigger than the error mean sum of squares are more in design 2 compared to design 1. Therefore, chances of showing a statistically significant difference are higher in design 2 compared to design 1.
This is equivalent to saying that design 2 is more competent than design 1. They may be different or nearly equal but not identical in most of the cases. If the trial is run under tightly controlled conditions and the number of subjects is large enough, no matter how small the difference between the formulations and it will be detected as significant.
The difference may give rise to following anomalies due to a large difference between two formulations, sample size not large enough Table 5. Evaluation of bioavailability and bioequivalence studies will be based upon the measurement of concentrations of the active drug substances in the plasma with respective of time. In some situations, the measurements of an active or inactive metabolite may be necessary.
These situations include where the concentrations of the drugs may be too low to accurately measure in the biological matrix, limitations of the analytical method, unstable drugs, and drugs with a very short half-life. Next 5 Tips associated with effective Regulatory medical writing. About The Author. Icbio Cro. Related Posts.
0コメント