Bioavailability & Bioequivalence Studies

Bioavailability & Bioequivalence studies
Hussein Talal
Done By: & ID NO. &
Sarmad Usama
201117011
201127022
Supervised by: Ashok Shakya

Introduction
Bioequivalence is a comparison of bioavailability of two or more product i.e. Formulation containing the same active ingredient are said to be bioequivalent if their rate & extent of absorption is same. One of the best way to compare two product is by clinical studies. But performing clinical studies is extremely cumbersome & expensive. Hence Bio-equivalence studies are generally used to compare two products so as to compare their biological equivalence. Bioequivalence is established if the in-vivo bioavaliability of test drug product (usually generic product) does not differ significantly in rate & extent of drug absorption, from reference listed drug (brand name product) administered at same dose, under similar experimental conditions.

Definitions
1. Bioavailability Means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. 2. Bioequivalence: The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

Definitions
3. Pharmaceutical equivalents Medicinal products are pharmaceutical equivalents if they contain the same amount of the same active substance(s) in the same dosage forms that meet the same or comparable standards. Pharmaceutical equivalence does not necessarily imply bioequivalence as differences in the excipients and/or the manufacturing process can lead to faster or slower dissolution and/or absorption. 4. Therapeutic equivalents A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and, clinically shows the same efficacy and safety as that product, whose efficacy and safety has been established.
Study Compound Reference Compound Cmax
Concentration
AUC Area under the concentration- time curve Cmax Maximum concentration Tmax Time to maximum concentration
AUC
Tmax Time

Need for Conducting BA/BE Studies
BA To evaluate the absolute systemic availability of active drug substance from a dosage form To determine the linearity of the bioavailability parameters over the proposed clinical dose range To study the effect of food on bioavailability BE When the proposed marketed dosage form is different from that used in pivotal clinical trials When significant changes are made in the manufacture of the marketed formulation When a new generic formulation is tested against the innovator's marketed product

Approaches for Determining Bioequivalence
1. In vivo measurement of active moiety or moieties in biologic fluid
2.
3.
In vivo pharmacodynamic comparison

In vivo limited clinical comparison
4.
In vitro comparison

A. Pharmacokinetic Studies Design and conduct of studies
The design should be based on a reasonable knowledge of the pharmacodynamics and/or the pharmacokinetics of the active substance in question. For the pharmacokinetic basis of these studies reference is made to the recommendation Pharmacokinetic studies in man. The design and conduct of the study should follow EC- rules for Good-Clinical Practice including reference to an Ethics Committee.

A. Pharmacokinetic Studies Design
Bioequivalence study should be designed in such away so as to identify treatment effects that are produced after administration of products. Two types of design 1. Crossover 2. Parallel
Generally crossover is used in practice in this design both test and reference product are compared in each subject that is each subject act as his/her own control In this design first subjects are randomly divided in to 2 groups and sequence of drug is randomly assigned.

If there are two formulations test (T) and reference (R) ; in period 1 , group 1 will receive T followed by R. Time period between administrations of two formulations will be sufficiently long considering adequate wash out period. Wash out period is essential to ensure complete elimination of drug before next administration.
10 half lives ensures more than 99% of elimination and hence wash out period should be at least 10 half lives.

Group II will start after completion of wash out period now in period II, group 1 will receive R followed by T . If drug require washout period of 7 days then sequence of administration of 2 formulation can be shown as:
Figure. Showing Concentrations After Two Separate Drug Administrations

For bioequivalence study in human volunteers, a Latin square cross over design is used It Compares 3 different drug formulations- A,B,& C. In this design , each subject receives each drug product only once
Latin Square Cross Over Design for bioequivalence study of 3 drug products in 6 human volunteers
SUBJECT STUDY PERIOD 1 STUDY PERIOD 2 STUDY PERIOD 3
1 2 3 4 5 6
A B C A C B
B C A C B A
C A B B A C

Designs used in BA/BE Trials 1. 2. 3. Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed Multiple-dose, two-way crossover, fed

A. Pharmacokinetic Studies Subjects: Selection of Volunteers
Typical Inclusion Criteria: 20-40 years of age Body weight + 10% of the desirable weight for height and frame Stable health (ECG, physical examination, blood and urine tests) Typical Exclusion Criteria History of drug abuse A disease/condition that would contraindicate taking the investigational drug Conditions requiring concomitant medication

Typical Exclusion Criteria Medication or drug use within 1 month prior to study initiation with any agent known to induce or inhibit drug-metabolizing enzymes Medications or drug use of any kind, including OTC medication within one week prior to study initiation A positive laboratory test for Hepatitis B surface antigen or urine screen for drugs of abuse Smokers

Typical Exclusion Criteria Donation of blood within 60 days prior to study initiation Significant psychiatric disorders A history of hypersensitivity of intolerance.

Subjects: Selection of Volunteers
Blinding If possible, the study should be conducted in such a way that the subject is not aware of which product is administered. Furthermore, the person checking for adverse reactions and the person conducting the analysis of samples must not know which product was administered.

A. Pharmacokinetic Studies Standardization of the study
All meals and fluids taken after the treatment should be standardized in regard to composition and time of administration. The subjects should abstain from drugs food and drinks, which may interact with circulatory, gastro-intestinal, liver or renal function As the bioavailability of an active substance from a dosage form could be dependent upon gastrointestinal transit times and regional blood flows, posture and physical activity may need to be standardized.

A. Pharmacokinetic Studies Sampling
Blood samples in principle should be used, urine samples also can be used. Blood samples should be taken at a frequency sufficient for assessing Cmax, AUC, tmax and other parameters. The duration of blood or urine sampling in a study should be sufficient to account for at least 80 percent of the known AUC to infinity (AUCI). This period is usually at least three times the terminal half-life of the drug.
To permit Calculation of the relevant pharmacokinetic parameters, from 12 to 18 samples should be collected per subject per dose.

A. Pharmacokinetic Studies Characteristics to be investigated
In most cases evaluations of bioavailability and bioequivalence will be based upon the measured concentrations of the active drug substance(s) in the biological matrix. In some situations, however, the measurements of an active or inactive metabolite may be necessary. These situations include where the concentrations of the drug(s) may be too low to accurately measure in the biological matrix, unstable drug(s), drug(s) with a very short half-life or in the case of prodrugs.

The plasma-time concentration curve is mostly used to assess the rate and extent of absorption of the study drug.
These include pharmacokinetic parameters such as the Cmax, Tmax

For single-dose studies, estimates of the following pharmacokinetic parameters must be tabulated for each combination of subjects and formulations: Cmax Maximum observed concentration. tmax Sampling time at which Cmax occurred. AUCT The area under the curve to the last quantifiable concentration calculated from observed data at specific time points. AUCI Area to infinity = AUCT + CT/, where CT is the estimated concentration at LQCT.
Percent of the area measured by AUCT relative to the extrapolated AUCI.

AUCRefTmax Area under the curve, for a test product, to the tmax of the reference product, calculated for each study subject. Terminal disposition rate constant TLIN Time point where log-linear elimination begins. LQCT Lowest Quantifiable Concentration Time. Time at which the last concentration occurred that is above the lower limit of quantitation. t Drug half-life = ln(2)/ = 0.693/.
Parameter Definitions Parameter Definition
Cmax
tmax AUCt
Maximum observed concentration (ng/mL).

Sampling time at which Cmax occurred (h). Area under the raw concentration versus time curve calculated using the trapezoidal rule from time 0 to LQCT (ngh/mL). Area to infinity = AUCT + CT/ where CT is the estimated concentration at LQCT (ngh/mL). Percent of the area measured by AUCT relative to the extrapolated total AUC. Terminal disposition rate constant calculated from the points on the log-linear end of the concentration versus time curve (h-1). Time point where log-linear elimination begins (h). Lowest Quantifiable Concentration Time. Time at which the last concentration occurred that is above the lower limit of quantitation (h). Drug half-life = ln2/ = 0.693/ (h).
AUCI AUCT X 100AUCI
TLIN
LQCT
T1/2
Figure: Illustration of the key metrics in a comparative bioavailability trial showing, for example, Test and Reference products. The maximum concentration (Cmax) occurs at the Tmax. The AUCt is the total area under the concentration versus time profile to the last sampling time. The area to time infinity (AUC) is the extrapolated area based on the AUCt and the terminal constant (z).
randomization Scheme of the Cross-over Design for the Comparison of Test (T) Versus Reference (R) Formulations
Subject
Number ID Sequence
Period
May 14, 1988 May 21, 1988
001
002 003 *004 005 006 007 008 009 **010
A
B C D E F G H T I
TR
RT RT TR TR RT TR RT TR RT
T
R R T T R T R T -
R
T T R T R T R -
Parameter Estimates for Each Subject Given the Test Formulation TEST FORMULATIONS AUC T AUC I Cmax(ng/ AUC T tmax(h) (ng. h/m (ng. h/m mL) (%) L) L)
ID
Seq
Period
(h- 1) TLIN (h) LQCT (h) t (h)
A B C E
TR RT RT TR
14 May 21 May 21 May 14 May
122 102 202 59
1.50 1.50 0.66 3.00
365 405 703 233
409 432 774 256
89 94 91 91
0.3002 0.2384 0.1776 0.3680
2.0 3.0 4.0 3.0
8.0 12.0 12.0 8.0
2.3 2.9 3.9 1.9
RT
21 May
66
1.00
247
265
93
0.3902
3.0
8.0
1.8
Parameter Estimates for Each Subject Given the Reference Formulation REFERENCE FORMULATION AUC T AUC I Period C (ng/ AUC I max tmax(h) (ng .h/m (ng .h/m mL) (%) L) L)
ID
Seq
(h- 1 ) TLIN (h) LQCT (h) t (h)A
A B
TR RT
21 May 14 May
126 207
1.50 1.50
375 595
418 613
90 97
0.2660 0.2900
3.0 3.0
8.0 12.0
2.6 2.4
C
E F
RT
TR RT
14 May
21 May 14 May
123
37 85
1.50
1.00 2.00
471
190 257
492
224 285
96
85 90
0.2666
0.2653 0.3114
4.0
3.0 3.0
12.0
8.0 8.0
2.6
2.6 2.2

A. Pharmacokinetic Studies Chemical analysis
The bioanalytical methods used to determine the active principle and/or its metabolites in plasma, serum, blood or urine or any other suitable matrix must be well characterised, fully validated and documented to yield reliable results that can be satisfactorily interpreted.
The main objective of method validation is to demonstrate the reliability of a particular method for the quantitative determination of an analyte(s) concentration in a specific biological matrix.

A. Pharmacokinetic Studies Chemical analysis
The characteristics of a bioanalytical method essential to ensure the acceptability of the performance and reliability of analytical results are stability of the Drug/Metabolite in the biological matrix specificity Specificity/selectivity Sensitivity Precision and Accuracy response function. Range & Linearity
1. 2. 3. 4. 5. 6.

A. Pharmacokinetic Studies Statistical Evaluation
1. Data analysis:
The primary concern in bio-equivalence assessment is to limit the consumers risk i.e., erroneously accepting bioequivalence and also at the same time minimizing the manufactures risk i.e., erroneously rejecting bioequivalence. This is done by using appropriate statistical methods for data analysis and adequate sample size.

2. Statistical analysis:
The statistical procedure should be specified in the protocol itself.
The statistical analysis (e.g. ANOVA) should take into account sources of variation that can be reasonably assumed to have an effect on the response.

2. Statistical analysis:
To meet the assumption of normality of data underlying the statistical analysis, the logarithmic transformation should be carried out for the pharmacokinetic parameters Cmax and AUC before performing statistical analysis. The analysis of Tmax is desirable if it is clinically relevant.

3. Criteria for bioequivalence:
To establish Bioequivalence, the calculated 90% confidence interval for AUC and Cmax should fall within the bioequivalence range, usually 80-125%.
The non-parametric 90% confidence interval for Tmax should lie within a clinically acceptable range.

B. Pharmacodynamic Studies
Used for establishing equivalence between two pharmaceutical products.
These studies may become necessary if quantitative analysis of the drug and/or metabolite(s) in plasma or urine cannot be made with sufficient accuracy and sensitivity. Required if measurements of drug concentrations cannot be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product.

C. In Vitro studies
In vitro dissolution study may be sufficient to demonstrate equivalence between two drug products. The test methodology adopted should be in line with the pharmacopoeial requirements Dissolution studies should generally be carried out under mild agitation conditions at 370.5C and at physiologically relevant pH. More than one batch of each formulation should be tested. Comparative dissolution profiles, rather than single point dissolution test data, should be generated.

Study report
The report should include (as a minimum) the following information
A. Table of contents
B. Title of the study
C.
Names and credentials of responsible investigators
D. Signatures of the principal and other responsible authenticating their respective sections of the report E. Site of the study and facilities used

Study report
F. The report should include (as a minimum) the following information The period of dates over which the clinical and analytical steps were conducted
G. Names and batch numbers of the products compared
H. A signed declaration that this was identical to that intended for marketing.
I. J. Results of assays and other pharmaceutical tests Full protocol for the study including a criteria for inclusion/exclusion or withdrawal of subjects

Study report
The report should include (as a minimum) the following information
K. L.
Demographic data of subjects Names and addresses of subjects
M. Details of analytical methods used, full validation data, quality control data and criteria for accepting or rejecting assay results N. Representative chromatograms covering the whole concentration range for all, standard and quality control samples as well as specimens analysed O. Sampling schedules and deviations of the actual times from the scheduled P. Details of how pharmacokinetic parameters were calculated

Conclusion
During the last few years, there is a major progress in policies and procedures concerning the determination of bioequivalence Presently, there ibis international harmonization of regulatory requirements for bioequivalence studies However, the trend in the near future appears towards achieving the appropriate choice of clinically relevant bioequivalence ranges based on therapeutic ranges, rate of absorption metrics, designs to resolve the issue of intra and inter subject variability.
Thank you
References
1-GUIDELINES FOR BIOAVAILABILITY BIOEQUIVALENCE STUDIES Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India New Delhi. 2-MALAYSIAN GUIDELINES FOR THE CONDUCT OF BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES 3-Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2003 4-BIOAVAILABILITY & BIIOEQUIIVALENCE TRIALS Shubha Ranii, Ph.D. http://www.synchronresearch.com/pdf_files/ba-be-trials.pdf
5-Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guideld/bio/gd_cbs_ebc_ld-eng.php

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Bioavailability & Bioequivalence studies

Supervised by: Ashok Shakya