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Method of studying Bioavailability and Bioequivalence:

Method of studying Bioavailability and Bioequivalence GUIDED BY: Dr. R.K.PARIKH Presented by: Sanket patel M. Pharm SEM-I Roll no. - 04 PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 1 /42

contents:

contents Definition Method for studying bioavailability Method for studying bioequivalence Recent study PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 2 /42

Bioavailability:

Bioavailability Indicates a measurement of the rate & extent of therapeutically active drug that reaches the systemic circulation PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 3 /42

Bioequivalence (BE): Definition:

Bioequivalence (BE): Definition “ T he 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 .” PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 4 /42

Pharmaceutic equivalents:

Pharmaceutic equivalents Drug products that contain the same active ingredient (same salt, ester, or chemical form) & are identical in strength/conc., dosage form and route of administration Also chemical equivalents Must meet identical standards (strength, quality, purity and identity) but may differ in characteristics (e.g. color, flavor, shape, packaging, preservatives PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 5 /42

Therapeutic equivalents:

Therapeutic equivalents Drug products that contain the therapeutically active drug theat should give the same therapeutic effect & have equally potent ial for adverse effects Therapeutic drug products may differ in certain characteristics (e.g. color, flavor, packaging PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 6 /42

Those requiring bioavailability studies:

Those requiring bioavailability studies Unmarketed drugs which do not have full NDA (new drug application) New formulations of active drug ingredients or therapeutic moieties that have full NDA approval & are approved for marketing PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 7 /42

Slide 8:

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Methods of Assessing Bioavailability::

Methods of Assessing Bioavailability: 1. plasma data a. tmax - time of peak plasma concentration - the time required to reach the maximum drug concentration after drug administration - unit: ? PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 9 /42

Slide 10:

b. Cmax – maximum plasma drug concentration obtained after oral administration of the drug - indicates that the drug sufficiently and systematically absorbed to provide a therapeutic response - approximate the absorption rate of a drug - unit: ? PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 10 /42

Slide 11:

c. AUC Area Under the Curve Area under the plasma level time curve AuC 1 = C 0 + C 1 ∙ t 1 - t 0 2 PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 11 /42

Slide 12:

c. AUC Measure of quantity of drug in the body If one knows the AUC for a given dose size upon IV administration of a drug, the fraction of drug absorbed (F = absolute bioavailability) upon EV route of administration can be calculated from the AUC obtained by the latter route Measures the extent of bioavailability PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 12 /42

Slide 13:

Estimates on the relative magnitude of the AUC can be obtained by either of the following methods: 1. counting method 2. weighing method PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 13 /42

Slide 14:

Exact calculation of the AUC is done by the following method: 1. trapezoidal rule Trapezoidal rule: compute for the individual area of the trapezoids. Total AUC = 0 → infinity Infinite time – time beyond which the area is insignificant PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 14 /42

AUC Profile:

AUC Profile serum conc (µg/ml) time after drug adm (hrs) 1.0 0.5 2.0 1 4.0 2 3.8 3 3.5 4 2.0 6 1.75 8 0.75 10 0.50 12 1. illustrate AUC by plotting the data serum conc vs time 2. compute for AUC EV & AUC IV 3. compute for total AUC PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 15 /42

Informations that we can get from a typical conc-time curve :

Informations that we can get from a typical conc-time curve MEC – min. conc. required by the receptors to produce the desired effect MTC – min. conc. needed to just barely produce toxic effect Desired therapeutic range (therapeutic window) – distance between MEC and MTC; it is where the drug produces its characteristic effects Onset time – time required for drug to reach MEC PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 16 /42

Slide 17:

Duration of action – the difference between onset time and the time for the drug to decline back to MEC; length of time the drug level remains above MEC Intensity – proportional to the number of receptors occupied, the higher the plasma conc. produced, the greater pharmacologic response up to a maximum PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 17 /42

2. urine data:

2. urine data Xu – cumulative amount of drug excreted in the urine - tells us how much drug is present in the urine - directly related to the total amount of drug absorbed. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 18 /42

Slide 19:

b. rate of drug excretion in the urine dXu dt - dependent on the first order kinetics and the plasma concentration c. time for the maximum urinary excretion (tºº) - PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 19 /42

Slide 20:

When to validly apply the plasma & urine data - comparing the relative performance of a single drug 1. different physical forms 2. different dosage forms 3. different dosage regimen/size of doses 4. different routes of administration 5. different subjects PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 20 /42

Slide 21:

3. acute pharmacologic effect 4. clinical response - toxicity - no response - therapeutic failure - good therapeutic response PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 21 /42

Slide 22:

The primary proof of drug availability is the Clinical Efficacy – measured by quantification of biological response The need for a large number of subjects to obtain a reliable statistical data is the difficulty encountered in quantitating biological response because of the variability in patient response PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 22 /42

CLINICAL PROFILE:

CLINICAL PROFILE Used to compare clinical efficacy of two or more drugs on certain indication. Plot of the clinical response vs time after administration can be established PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 23 /42

Slide 24:

Statistical analysis can be used to determine if there is a significant difference between the variables. Disadvantages of clinical studies: 1. tedious 2. complex 3. expensive PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 24 /42

Bioequivalence:

Bioequivalence demonstrate that other drug products are comparable with respect to biologic performance to an already approved drug product. When a generic formulation is tested against an innovator brand When significant changes are made in the manufacture of the marketed formulation PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 25 /42

DIFFERENT METHODS OF STUDYING BIOEQUIVALENCE: :

DIFFERENT METHODS OF STUDYING BIOEQUIVALENCE: IN VIVO BIOEQUIVALENCE STUDY PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 26 /42 CROSS OVER DESIGN PARALLEL GROUP DESIGN Between subject variability does not enter into the error variability Between subject variability is very much and is included in error Number of subjects required are less Number of subjects required are more If observations are missing design loses efficiency The statistical analysis is simple even if some results are missing The trial will be too consuming If the investigated drug and/or time metabolite have long half life, this design can be used

CROSS OVER DESIGN:

CROSS OVER DESIGN Drug Product Subject Study Period 1 Study Period 2 Study Period 3 1 A B C 2 B C A 3 C A B 4 A C B 5 C B A 6 B A C LATIN SQUARE CROSS OVER DESIGN Study Design PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 27 /42

REPLICATED CROSS OVER DESIGN :

REPLICATED CROSS OVER DESIGN Period 1 Period 2 Period 3 Period 4 Sequence 1 T R T R Sequence 2 R T R T PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 28 /42 Period refers to the time period in which a study is performed. A sequence refers to the number of different orders in the treatment groups in a study.

Advantages of Cross over design:

Advantages of Cross over design Minimize intersubject variability in plasma drug level. Minimize intrasubject variability → affecting bioavailability of a subsequently administered product. Minimize variation due to time effect. Make it more possible to focus more on formulation variables which is the key to success for any bioequivalence study. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 29 /42

EVALUATION OF THE DATA: :

EVALUATION OF THE DATA: Analytical Method: Pharmacokinetic Evaluation of the Data Statistical Evaluation of the Data Analysis of Variance (ANOVA) PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 30 /42

Two One-Sided Tests Procedure :

Two One-Sided Tests Procedure The two one-sided tests procedure is also referred to as the confidence interval approach (). This statistical method is used to demonstrate if the bioavailability of the drug from the Test formulation is too low or high in comparison to that of the Reference product. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 31 /42

Drawbacks of cross-over design:- :

Drawbacks of cross-over design:- Takes long time since appropriate washout period between 2 administrations is essential. Time may be longer if the drug has t 1/2 long. When the no. of formulations to be tested are more, the study becomes more difficult and subject dropout rate may increase. This can be overcome by use of a balanced incomplete design in which a subject receives no more that two formulations PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 32 /42

IN VITRO BIOEQUIVALENCE STUDY :

IN VITRO BIOEQUIVALENCE STUDY Dissolution study PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 33 /42

PHARMACODYNAMIC STUDIES: :

PHARMACODYNAMIC STUDIES: If quantitative analysis of the drug and/or metabolite(s) in plasma or urine cannot be made with sufficient accuracy and sensitivity. If measurement of drug concentrations cannot be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product e.g. topical products without an intended absorption of the drug into the systemic circulation. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 34 /42

COMPARATIVE CLINICAL TRIALS :

COMPARATIVE CLINICAL TRIALS The plasma concentration time-profile date may not be suitable to assess equivalence between two formulations. Pharmacodynamic studies cannot be performed because of lack of meaningful pharmacodynamic parameters, which can be measured. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 35 /42

Bioequivalence studies for controlled release Product :

Bioequivalence studies for controlled release Product For controlled release products administered once a day, a three way cross over study comparing the test formulation with an approved controlled release drug product under fasting conditions is conducted to ensure controlled release nature of the test product as well as the absence of dose dumping. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 36 /42

Following are the cases where bioequivalence studies are not necessary:

Following are the cases where bioequivalence studies are not necessary a) An aqueous solution for parenteral use b) A solution for oral use c) A gas d) A powder for reconstitution as a solution for oral or parenteral use e) An otic or ophthalmic solution f) A topical aqueous solution g) An inhalation product or nasal spray as an aqueous solution PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 37 /42

Bioequivalence of Topical Formulations in Humans:

Bioequivalence of Topical Formulations in Humans PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 38 /42 Linear microdialysis probes in situ in the dermis. The length accessible to microdialysis sampling is 3 cm. A microdialysis pump provides the perfusate flow of 1.25 l/minute. Samples of 25 l are collected every 20 minutes for 5 hours. At t =0, the topical formulation is applied in a dose of 4 mg/cm 2 and left throughout the experiment. Microdialysis technique

DPK method:

DPK method In the determination of BE of topical products, the method of choice is the tape-stripping technique, also called the DPK method The method consists of a standardized protocol of repeated applications and removal of adhesive tape on the skin surface, whereby consecutive layers of SC cells are sampled. PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 39 /42

Recent study: Bioequivalence Study of Metformin Hydrochloride Tablets 1000 mg Tablets of Dr. Reddy's Laboratories Limited Under Fed Condition :

Recent study : Bioequivalence Study of Metformin Hydrochloride Tablets 1000 mg Tablets of Dr. Reddy's Laboratories Limited Under Fed Condition First Received: July 9, 2010   Last Updated: July 12, 2010 Study Design: Allocation: Randomized Control: Active Control Endpoint Classification: Bio-equivalence Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 40 /42

Bioequivalence study and bioanalytical method development of Levofloxacin tablets in albino rat plasma using RP-HPLC method:

Bioequivalence study and bioanalytical method development of Levofloxacin tablets in albino rat plasma using RP-HPLC method Archives of Applied Science Research, 2010, 2 (4): 103-110 PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 41 /42

CHARACTERIZATION AND PERMEATION STUDIES OF DILTIAZEM HYDROCHLORIDE-FICUS RETICULETA FRUIT MUCILAGE TRANSDERMAL PATCHES:

CHARACTERIZATION AND PERMEATION STUDIES OF DILTIAZEM HYDROCHLORIDE- FICUS RETICULETA FRUIT MUCILAGE TRANSDERMAL PATCHES Volume 1, Issue 2, March – April 2010; Article 007 In-vitro penetration studies were performed in a Keshary-Chien diffusion cell PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 42 /42

Referances:

Referances . D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokin. Biopharm. 15:657-680 (1987). . W. W. Hauck and S. Anderson. A new statistical procedure for testing equivalence in two-group comparative bioavailabflity trials. J. Pharmacokin. Biopharm. 12:83-91 (1984). www.ajpe.org/legacy/pdfs/aj630215.pdf www.springerlink.com/ www.omicsonline.org ( Shah et al. , 1998 ; Food and Drug Cosmetics Act, 2002 ). PAPER NO.910102/22-12-2010 SANKET PATEL l/M.PHARM SEM-I/L.M.COLLEGE OF PHARMACY 43 /42