Bioavailability and bioequivalance studies


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Bioavailability and bioequivalance studies

  3. 3. • Ensuring uniformity in standard of quality safety and efficacy ofpharmaceutical product is a matter of concern.•Bioavailability of a pharmaceutical product should be known andreproducible.•BE/BA data is required to be furnished during new drug applicationas per schedule Y.•Both bioavailability and bioequivalence focus on the release of adrug substance from its dosage form and subsequent absorptioninto the systemic circulation.•For this reason, similar approaches to measuring bioavailabilityshould generally be followed in demonstrating bioequivalence.3
  4. 4. •Bioavailability can be generally documented by a systemic exposureprofile obtained by measuring drug and/or metabolite concentrationin the systemic circulation over time.•Bioequivalence studies should be conducted for the comparison oftwo medicinal products containing the same active substance.• Several test methods are available to assess equivalence, including : comparative bioavailability (bioequivalence) studies, in which theactive drug substance or one or more metabolites is measured in anaccessible biological fluid such as plasma, blood or urinecomparative pharmacodynamic studies in humans comparative clinical trials in-vitro dissolution tests4
  5. 5. •In vivo bioequivalence/bioavailability studies recommended forapproval of modified release products should be designed to ensurethat –The product meets the modified release label claims.The product does not release the active drug substance at a rateand extent leading to dose dumping.There is no significant difference between the performance of themodified release product and the reference product, when given indosage regimes to arrive at the steady state.There must be a significant difference between the performance ofmodified release product and the conventional release product whenused as reference product.5
  6. 6. •BIOAVAILABILITYBioavailability refers to the relative amount of drug from anadministered dosage form which enters the systemic circulationand the rate at which the drug appears in the systemic circulation.•BIOEQUIVALENCEBioequivalence of a drug product is achieved if its extent and rateof absorption are not statistically significantly different from thoseof the reference product when administered at the same molardose.6
  7. 7. PHARMACEUTICAL EQUIVALENTSPharmaceutical equivalents are drug products that contain identicalamounts of the identical active drug ingredient, i.e., the same salt orester of the same therapeutic moiety, in identical dosage forms, but notnecessarily containing the same inactive ingredients.PHARMACEUTICAL ALTERNATIVESPharmaceutical alternatives are drug products that contain the identicaltherapeutic moiety, or its precursor, but not necessarily in the sameamount or dosage form or as the same salt or ester.SUPRA-BIOAVAILABILITYThis is a term used when a test product displays an appreciably largerbioavailability than the reference product.7
  8. 8. THERAPEUTIC EQUIVALENTSTherapeutic equivalents are drug products that contain the sameactive substance or therapeutic moiety and, clinically show thesame efficacy and safety.SCOPE OF THE GUIDELINESBioavailability and Bioequivalence studies are required byregulations to ensure therapeutic equivalence between apharmaceutically equivalent test product and a referenceproduct.8
  9. 9. 1. When bioequivalence studies are necessary and types of studies required –a) In vivo studies :For . Oral immediate release drug formulations with systemic action when one ormore of the following criteria apply:-1. Indicated for serious conditions;2. Narrow therapeutic window/safety margin;3. Pharmacokinetics complicated by variable or incomplete absorptionor absorption window,4. Unfavorable physicochemical properties,5. Documented evidence for bioavailability problems related to thedrug ordrugs of similar chemical structure or formulations;6. Where a high ratio of excipients to active ingredients exists.9
  10. 10. For Non-oral and non-parenteral drug formulations designed to act bysystemic absorption (such as transdermal patches, suppositories, etc.).For Sustained or otherwise modified release drug formulationsdesigned to act by systemic absorption.For Fixed-dose combination products with systemic action.For Non-solution pharmaceutical products which are for non-systemicuse (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and areintended to act without systemic absorption.10
  11. 11. B. In vitro studies :For Drugs for which the applicant provides data to substantiate all ofthe following :a. Highest dose strength is soluble in 250 ml of an aqueous media overthe pH range of 1-7.5 at 37°C.b. At least 90% of the administered oral dose is absorbed on massbalance determination or in comparison to an intravenous referencedose.c. Speed of dissolution as demonstrated by more than 80% dissolutionwithin 15 minutes at 37°C using IP apparatus 1, at 50 rpm or IPapparatus 2, at 100 rpm.For . Different strengths of the drug manufactured by the samemanufacturer, where all of the following criteria are fulfilled:a. the qualitative composition between the strengths is essentially thesame.11
  12. 12. B. The ratio of active ingredients and excipients between the strengths isessentially the same,C. The method of manufacture is essentially the sameD. An appropriate equivalence study has been performed on at least oneof the strengths of the formulationE. In case of systemic availability - pharmacokinetics have been shownto be linear over the therapeutic dose range.NOTE :In each comparison, the new formulation or new method ofmanufacture shall be the test product and the prior formulation (orrespective method of manufacture) shall be the reference product.12
  13. 13. When bioequivalence studies are not necessary :A. When new drugs are to be administered parent rally (e.g.,intravenous, intramuscular, subcutaneous, intrathecaladministration etc.) as aqueous solutions and contain the same activesubstance(s) in the same concentration and the same excipients incomparable concentrations;B. When the new drug is a solution for oral use, and contains theactive substance in the same concentration, and does not contain anexcipients that is known or suspected to affect gastro-intestinal transitor absorption of the active substance;C. When the new drug is a gas;D. When the new drug is an optic or ophthalmic or topical productprepared as aqueous solution and contains the same activesubstance(s) in the same concentrationE. When the new drug is a powder for reconstitution as a solution andthe solution meets either criterion (a) or criterion (b) above.13
  14. 14. BE /BA studies are generally classified asPharmacokinetic endpoint studies.Pharmacodynamic endpoint studies.Clinical endpoint studies.In vitro endpoint studies .14
  15. 15. 15
  17. 17. 1. Pharmacokinetic Studies:1. A ) Study Design :The basic design of an in-vivo bioavailability study is determined by thefollowing:• What is the scientific question(s) to be answered.• The nature of the reference material and the dosage form to be tested.• The availability of analytical methods.• Benefit-risk ratio considerations in regard to testing in humans.1. B ) Study Population :• The number of subjects recruited should be sufficient to allow forpossible withdrawals or removals (dropouts) from the study.• The minimum number of subjects should not be less than 16 unlessjustified for ethical reasons.•The significance level desired: usually 0.05.17
  18. 18. 1.C ) Selection Criteria for Subjects :•To minimize intra and inter individual variation subjects should bestandardized as much as possible and acceptable.•The studies should be normally performed on healthy adult volunteerswith the aim to minimize variability and permit detection of differencesbetween the study drugs.•Women should be required to give assurance that they are neitherpregnant, nor likely to become pregnant until after the study.• Studies on teratogenic drugs should be conducted only on males.For drugs where the risk of toxicity or side effects is significant, studiesmay have to be carried out in patients with the concerned disease, butwhose disease state is stable.18
  19. 19. 1.D ) Study Conditions :A. . Selection of Blood Sampling Points/SchedulesThe blood-sampling period in single-dose trials of an immediate releaseproduct should extend to at least three-elimination half-lives.•There should be at least three sampling points during the absorptionphase, three to four at the projected Tmax, and four points during theelimination phase.Where urinary excretion is measured in a single-dose study it isnecessary to collect urine for seven or more half-lives.•The area extrapolated from the time of the last measured concentrationto infinite time is only a small percentage (normally less than 20%) ofthe total AUC .B. Fasting and Fed State Considerations• A single dose study should be conducted after an overnight fast (atleast 10 hours), with subsequent fast of 4 hours following dosing.19
  20. 20. • For multiple dose fasting state studies, when an evening dose must begiven, two hours of fasting before and after the dose is consideredacceptable.• When it is recommended that the study drug be given with food orwhere the dosage form is a modified release product, fed state studiesneed to be carried out in addition to the fasting state studies.•Studies in the fed state require the consumption of a high-fatbreakfast 15 min before dosing.C. Steady State Studies•Where the drug has a long terminal elimination half-life and bloodconcentrations after a single dose cannot be followed for a sufficienttime.•Where the drug is likely to accumulate in the body.•For drugs that exhibit non-linear pharmacokinetics.The dosing schedule should follow the clinically recommendeddosage regimen.20
  21. 21. 1.E ) Characteristics to be investigated during BE/BA study•Evaluations of BA/BE will be based upon the measured concentrations of theactive drug substance(s) in the biological matrix.•The measurements of an active or inactive metabolite may be necessary:a)where the concentrations of the drug(s) may be too low to accuratelymeasure in the biological matrix, (b) limitations of the analytical method, (c)unstable drug(s), (d) drug(s) with a very short half-life or (e) in the case ofprodrugs.•Racemates should be measured using an achiral assay method.•The plasma-time concentration curve is mostly used to assess the rate andextent of absorption of the study drug. This include Cmax, Tmax, AUC0-t andAUC0-∞.1.F ) Statistical Evaluation•The statistical analysis (e.g. ANOVA) should take into account sources ofvariation that can be reasonably assumed to have an effect on the response.•The logarithmic transformation should be carried out for thepharmacokinetic parameters Cmax and AUC before performing statisticalanalysis.21
  22. 22. •The parameter Tmax should be analyzed using non-parametricmethods.1.G) Criteria for bioequivalence•To establish Bioequivalence, the calculated 90% confidence intervalfor AUC and Cmax should fall within the bioequivalence range, usually80-125%.•Tighter limits for permissible differences in bioavailability may berequired for drugs that have:I A narrow therapeutic index.II A serious, dose-related toxicity.III A steep dose/effect curve, orIV A non-linear pharmacokinetics within the therapeutic dose range.22
  23. 23. 1.H) Immediate-release formulations• Generally a single-dose, non replicate, fasting study is done.• Food-effect studies are required:1) when it is recommended that the study drug should be taken withfood (as would be in routine clinical practice);2) when fasting state studies make assessment of Cmax and Tmax isdifficult.1 I) Modified-release formulations• Should conduct fasting as well as food-effect studies.• If multiple-study design is important, appropriate dosageadministered and sampling carried out to document attainment ofsteady state.23
  24. 24. The various types of test design that are employed are :1. COMPLETELY RANDOMISED DESIGNS ;• All treatments are randomly allocated among all experimentalsubjects.• Label all subjects with the same no. of digits, for e.g. 1 to 20.randomly select non repeating numbers from these labels for firsttreatment, and then repeat for all other treatment.2. RANDOMIZED BLOCK DESIGN ;• First the subjects are sorted into homogenous groups, called blocksand the treatments are then assigned at random within the block.3. CROSSOVER & CARRYOVER DESIGN;• The administration of two or more treatment one after other in aspecific or random order to the same group of patients .• Its drawback is carryover effect i.e. residual effect from precedingtreatments.• To prevent this wash out period is always allowed to eliminate mostof the drug from body.24
  25. 25. 4. LATIN SQUARE DESIGN;•It is a two factor design with one observation in each cell.•Here, the rows represent subject and column represent treatment.Fig ; Latin square design for 12 subject to compare 3 formulation A,B,CSubjectno.1,72,83,94,105,116,12StudyperiodIABCACBWashoutperiodStudyperiodIIBCABCAWashoutperiodStudyperiodIIICABBAC25
  26. 26. BIOWAIVERS ( exemptions) –In vitro studies ,i.e. dissolution studies can be used in place of in vivobioequivalence under certain conditions ,called BIOWAVIERS.1. The drug product differs only in strength of active substance,provided the following condition hold ;a) Pharmacokinetics are linear.b) The qualitative composition is same.c) The ratio between active substance and exepient is same.d) Both product are produced by same manufacturer at same site.e) A BA/BE study is performed with original product.2. The drug has been slightly reformulated or manufacturing methodhas been slightly modifies by same manufacturer in ways that canbe argues irrelevant for BA.3. The product meets following requirement ;26
  27. 27. a) The product is in form of solution or solublised form ( elixir, syrup)etc.b) The product contain active ingredient in same con as approved drug.c) The product contain no exepient known to significantly affectabsorption of active ingredient.d) The product is administered by inhalation as gas or vapor.e) The product is for oral administration but not intended forabsorption ( antacid or radio opaque medium ).f) The product is intended for topical administration ( ointment,creams, gels etc,) for local effect.27
  28. 28. 2. . Pharmacodynamic Studies•Studies in healthy volunteers or patients using pharmacodynamicparameters may be used for establishing equivalence between twopharmaceutical products;•These studies may become necessary : If quantitative analysis of the drug and/or metabolite(s) in plasma orurine cannot be made with sufficient accuracy and sensitivity; If drug concentration measurement cannot be used as surrogateendpoints for the demonstration of efficacy and safety of the particularpharmaceutical product.• Important specifications for pharmacodynamic studies include :I ) A dose-response relationship should be demonstrated;II) Sufficient measurements should be taken to provide an appropriatepharmacodynamic response profile;28
  29. 29. III) The complete dose-effect curve should remain below the maximumphysiological response;IV) All pharmacodynamic measurements/methods should be validatedfor specificity, accuracy, and reproducibility.• The response should be measured quantitatively under double-blindconditions and be recorded in a instrument-produced or instrument-recorded fashion on a repetitive basis to provide a record ofpharmacodynamic events which are a substitute for plasmaconcentrations.• A crossover or parallel study design should be used, as appropriate.•When pharmacodynamic studies are to be carried out on patients, theunderlying pathology and natural history of the condition should beconsidered in the study design.29
  30. 30. 3. Clinical endpoint studies or comparative clinical trials•In the absence of pharmacokinetic and pharmacodynamic approaches,adequate and well-controlled clinical trials may be used to establish BA/BE.•The number of patients to be included in the study will dependon the variability of the target parameters and the acceptance range, and isusually much higher than the number of subjects in bioequivalence studies.•The following items are important and need to be defined in the protocol inadvance:a. The target parameters which usually represent relevant clinical end-pointsfrom which the intensity and the onset, if applicable and relevant, of theresponse are to be derived.b. The size of the acceptance range has to be defined case-to- case taking intoconsideration the specific clinical conditions.C . The presently used statistical method is the confidence interval approach.d. Where appropriate, a placebo leg should be included in the design.e. In some cases, it is relevant to include safety end-points in the finalcomparative assessments.30
  31. 31. 4. In Vitro studies•In certain situations a comparative in vitro dissolution study may be sufficientto demonstrate equivalence between two drug products (biowaviers).•Dissolution studies should generally be carried out under mild agitationconditions at 37±0.5°C and at physiologically relevant pH.• More than one batch of each formulation should be test. Comparativedissolution profiles, rather than single point dissolution test data, should begenerated .• The design should include:Individually testing of at least twelve dosage units of each batch.Suitably spaced time points to provide a profile for each batch, e.g. at 10, 20and 30 minutes or as appropriate to achieve virtually complete dissolution.31
  32. 32. Determining the dissolution profile in at least three aqueous mediacovering the pH range of 1.0 to 6.8 or in cases where considerednecessary, Ph range of 1.0 to 8.0.Conducting the tests on each batch using the same apparatus and,if possible, on the same or consecutive days.32
  33. 33. •With respect to the conduct of bioequivalence/bioavailability studiesfollowing important documents must be maintained:A) Clinical Data :•All relevant documents as required to be maintained for compliancewith GCP Guidelines .B) Details of the analytical method validation including the following:a. System suitability testb. Linearity rangec. Lowest limit of quantizationd. QC sample analysise. Stability sample analysisf. Recovery experiment result33
  34. 34. C) Analytical data of volunteer plasma samples which should includethe following:a. Validation data of analytical methods used,b. Chromatograms of all volunteers,c. Inter-day and intra-day variation of assay results,d. Details including chromatograms of any repeat analysis performed,e. Calibration status of the instruments .D) Raw dataE) All comments of the chief investigator regarding the data of thestudy submitted for review.F) A copy of the final report34
  35. 35. 1. Guidelines for bioavailability & bioequivalence studies , central drugsstandard control organization , ministry of health & family welfare,government of India, new Delhi. (march 2005).2.Brahmankar D.M, Jaiswal Sunil B, Biopharmaceutics andpharmacokinetics , Vallabh prakshan , second edition , 2009, p.p 336-344.3. The basic regulatory considerations and prospects for conductingbioavailability/ bioequivalence (BA/BE) studies – an overview, Dove pressjournal, Comparative effectiveness journal, 21 march 2011.35
  36. 36. 36