study design for bioavailability and bioequivalence
TRANSCRIPT
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BABASAHEB BHIMRAO AMBEDKAR UNIVERSITY
PRESENTATION ON STUDY DESIGN AND STATISCAL CONCEPTS IN ESTIMATION OF BIOAVAILABILITY AND BIOEQUIVALENCE
Presented By: Priya SinghPresented To: Dr. Sonali Singh
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Bioavailability
Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
when a medication is administered intravenously, its bioavailability is 100%.
when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism).
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Types of Bioavailability
There are two types….1. Absolute bioavailability - It is the fraction of
the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug.
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1. Relative Bioavailability - Relative bioavailability measures the bioavailability (estimated as the AUC) of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug.
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Bioequivalence
Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug.
In order to determine that two medicines are bioequivalent there must be no more than a 20% difference between the AUC and Cmax.
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Assessment of Bioavailability
In vivo bioequivalence studies are conducted in the usual manner as discussed for bioavailability studies, i.e. ……
1. Pharmacokinetic Methods A. Plasma level-time study B. Urinary Excretion studies 2. Pharmacodynamic MethodsA. Acute pharmacological responseB. Therapeutic response
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Pharmacokinetic Methods
The parameter that are useful in determining the bioavailability of a drug from a drug product based on indirect methods…
Plasma data1. Time of peak plasma conc.( t max)2. Peak plasma conc.(Cmax)3. Area under the curve (AUC) Urine data1. Rate of drug excretion in the urine (dXu /dt)2. Cumulative amount of drug excreted in urine (Xu)3. Time for maximum urinary excretion (tu)
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Pharmacodynamics Methods
In order to estimate the bioavailability of a drug product accurately by this method, the following criteria should be met….
1. An established dose- related response curve 2. An easily measurable pharmacological response
such as heart rate, ECG, blood pressure, pupil diameter etc.
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Bioavailability Study Protocol
A. Study objectiveB. Study design Experimental design Wash out period Drug products (test and std) Route of drug administration Dosage regimen Frequency and duration of sampling Randomization of drug administration Single versus multiple dose study design
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Subjectsi. Healthy versus patientsii. Subject selection Medical history Physical examination Laboratory testiii. Study conditions Analysis of biological fluidsC. Methods of assessment of bioavailabilityD. Analysis and presentation of data
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PART 1
STUDY DESIGN FOR THE ASSESSMENT OF BIOAVAILABILITY AND BIOEQUIVALENCE
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Study Design
A good experimental design enhances the power of study.
It depends upon the question to be answered, nature of reference drug/dosage form and risk benefit ratio.
The study should be of cross over design and suitably randomized.
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Subject Selection
Healthy adult volunteers Age: 18-45 years Age/ sex representation corresponding to
therapeutic and safety profile. Women: pregnancy test prior to 1st and last dose
of study Teratogenic Drugs: male volunteers
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Study Conditions
The selected subjects should be maintained on a uniform diet and none of them should taken any drug at least one week prior to the study.
Fasting period before the administration. Standard diet to given after fasting, fluid intake
and volume to be allowed.
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Wash-out Period The time interval between two treatments is
called “wash-out period”. It is require for the elimination of the
administered dose of a drug so as to avoid carryover effect.
Washout period is a function of the half-life and the dose of the drug administered, the number of washout period in a study depends on type of cross-over design used and the number of formulations to be evaluated .
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Study Design
There are various study designs….1. Two Period cross-over design2. Latin Square Design3. Balance incomplete Block Design4. Parallel Group Design5. Replicate Cross-over study design
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Two Period Cross-over Design
For two formulations Even no. of subjects Randomly divided into 2 equal groups. First period, each member of one group receive a
single dose of the test formulation, each member of the other group receive the standard formulation.
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Subjects Period 1 Period 2
1-8 T S
9-16 S T
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Latin Square Design
For more than two Formulations. A group of volunteers will receive formulation in
sequence..Volunteer No.
Period 1 Period 2 Period 3
1 A B C
2 B C A
3 C A B
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Balance Incomplete Block Design (BIBD)
More than 3 formulations, Latin square design will not be ethically advisable
Because each volunteer mat require drawing of too many blood samples.
If each volunteer expected to receive at least two formulation, then such a study can be carried out using BIBD.
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Volunteer No. Period 1 Period 2
1 A B 2 A C 3 A D 4 B C 5 B D 6 C D 7 B A 8 C A 9 D A 10 C B 11 D B 12 D C
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Parallel- Group Design
Even no. of subjects in two groups. Each subject receive a different formulation. No washout necessary For drugs with long half life. This is also called as non- crossover study.
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Treatment A Treatment B
1 2 3 4 5 6 7 8 9 10 11 12
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Replicate Cross-over Study Design
For highly variable drugs Allows comparisons of within- subject variance Reduce the number of subjects needed Four period, two sequence, two formulation
design( recommended) Three period, two sequence ( partially
replicated )
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Period 1 2 3 4
Group A T R T R
Group B R T R T
Period 1 2 3
Group A T R T Group B R T R
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PART 2
STATISTICAL CONCEPTS IN ESTIMATION OF BIOAVAILABILITY AND BIOEQUIVALENCE
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Statistical Concepts
In our study statistical analysis will be performed on PK data of subjects by using SAS statistical software .
If they cannot be estimated, the subject will be excluded from the pertaining pharmacokinetic analysis. If necessary an unequal no. of subjects per sequence will be used
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Analysis of Variance
The various pharmacokinetic parameters (AUC (AUC 0-t and AUC 0-∞), Cmax) derived from the plasma concentration-time curve are subjected to ANOVA in which the variance is partitioned into components due to subjects, periods and treatments.
The classical null hypothesis test is the hypothesis of equal means: μT=μR (i.e. products are bioequivalent),
where - μT and μR represent the expected mean bioavailabilities of the test and reference formulations, respectively.
The alternate hypothesis therefore is H: μT ≠ μR (i.e. products are bioinequivalent)
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F - Test
An F test will be performed to determine the statistical significance of the effects involved in the model at a significance level of 5% (alpha=0.05).
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Ratio Analysis
Ratio of least squares means for test and reference listed drugs (RLD) formulations will be computed and reported for Log-transformed pharmacokinetic parameters C max, AUC (0-t) and AUC (0-∞).
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