Bioequivalence studies
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Bioequivalence studies

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Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency......

Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency with the original formulation is also mentioned.

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  • 1. Seminar onBIOEQUIVALENCE STUDIESPresented by:Muhammed Fahad1st M.PharmDept. of PharmaceuticsAl-Shifa College of Pharmacy
  • 2. BIOEQUIVALENCE STUDIES• To compare the bioavailability of the generic drugproduct to the brand-name product.• Bioequivalent drugs that have same systemicbioavailability will have same predictable drugresponse.• Still, variable response may occur due to age, drugtolerance, drug interactions or disease states.2
  • 3. Determining Bioequivalence• Test drug is bioequivalent if in vivo bioavailability oftest (generic drug) do not differ significantly(statistically insignificant) compared to reference(brand drug).• Done by measuring plasma drug concn, urinaryexcretion rates, pharmacodynamic effects, etc.3
  • 4. Neccessity to Establish Bioequivalence• Marketed drug products do not give comparabletherapeutic effects.• Narrow therapeutic ratio; requires careful dosing.• Serious adverse effect on the treatment (if notbioequivalent).• Low water solubility of active drug.• Slow dissolution rate.• High ratio of excipients to active ingredients (>5:1).4
  • 5. Neccessity to Establish BioequivalenceContd…• Active drug absorbed in particular segment of the GItract .• Absorption is less than 50%.• Rapid first-pass metabolism.• Drug is subject to dose-dependent kinetics.• Drug is rapidly metabolized or excreted.• Drug requires special coatings such as entericcoating.5
  • 6. DESIGN OF BIOEQUIVALENCE STUDIES The test and reference drug formulations mustcontain: pharmaceutically equivalent drug, in the same dose strength, in similar dosage forms (eg, immediate release orcontrolled release), and given by the same route of administration. Approval from Institutional Review Board (IRB) of thetesting unit. Consists of both single dose & multiple dose studies.6
  • 7. I. TitleA. Principal investigator(study director)B. Project/protocolnumber and dateII. Study objectiveIII. Study designA. DesignB. Drug products1. Test product(s)2. Reference productC. Dosage regimenD. Sample collection scheduleE. Housing/confinementF. Fasting/meals scheduleG. Analytical methodsIV. Study populationA. SubjectsB. Subject selection1. Medical history2. Physical examination3. Laboratory testsElements of a Bioavailability StudyProtocol7
  • 8. C. Inclusion/exclusion criteria1. Inclusion criteria2. Exclusion criteriaD. Restrictions/prohibitionsV. Clinical proceduresA. Dosage and drugadministrationB. Biological samplingschedule and handlingproceduresC. Activity of subjectsVI. Ethical considerationsA. Basic principlesB. Institutional review boardC. Informed consentD. Indications for subjectwithdrawalE. Adverse reactions andemergency proceduresVII. FacilitiesVIII. Data analysisA. Analytical validationprocedureB. Statistical treatment ofdataIX. Drug accountabilityX. Appendix8
  • 9. Analytical Methods• Must be accurate.• Of sufficient sensitivity to measure small changes.• Should be with appropriate precision.• Measure the actual concentration of the active drugor active metabolite(s), achieved in the body.9
  • 10. Reference Standard• One formulation of the drug is chosen as referencestandard against which all other formulations of thedrug are compared.• Reference drug should be administered by the sameroute as other drug formulations.• Reference standard is generally a formulationcurrently marketed with a fully approved NDA forwhich there are valid scientific safety and efficacydata.• Usually innovator’s or brand drug.10
  • 11. Extended-Release Formulations• Done in order to ensure that:1. Product has claimed controlled-release characters.2. No occurrence of dose-dumping.3. Steady state is equivalent to currently marketedextended release formulation.4. Consistent pharmacokinetic performance b/w units.New extended-release product  compared withexisting non-controlled release products.11
  • 12. Combination drug products• To determine the rate & extend of absorption of eachactive ingredient.• And to determine if it is equivalent to the rate andextent of absorption of each active ingredientadministered concurrently as separate single-ingredient preparations.12
  • 13. Study Designs1. Fasting study2. Food intervention study3. Multiple-dose (steady-state) study13
  • 14. Fasting Study• Done for immediate-release and modified-releaseoral dosage forms.• Male and female subjects may be used.• Blood sampling is done at appropriate intervals toobtain plasma drug concn—time profile.• Subjects should be in fasting condition—at least 10hrs before drug administration and 4 hrs afteradministration.14
  • 15. Food Intervention Study• Studies are conducted after high-fat and high-caloriemeal.• Subjects should be in fasting condition at least 10 hrsbefore drug administration.• Meal is given 30 minutes before dosing.• No food given for at least 4 hrs after administration.• Done for modified-release dosage forms.• And for immediate-release forms if bioavailabilty isaffected by food (e.g.. Ibuprofen, naproxen).15
  • 16. Multiple-Dose (Steady-State) Study• Done for oral extended-release (controlled-release)drug products.• Done in addition to the fasting & food interventionstudy.• Three consecutive Cmin measured on three consec:days to determine steady state.• Sampling done similar to fasting study.16
  • 17. Crossover Designs• Each subject receives the test & reference drugproduct.• Eg. Latin-square crossover designs.• Each subject receives each drug product only once.• Adequate wash-out period is provided b/w drugs.Advantages: Subject-to-subject variation is reduced. All patients do not receive same drug product on thesame day.17
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  • 20. • Period—time period in which a study is performed.• Two-period study – performed on 2 diff. days separatedby a washout period—generally about 10 eliminationhalf-lives.• Sequence—no. of diff orders in the treatment groupsin a study.• For e.g., a two-sequence, two-period study would bedesigned as follows:20
  • 21. EVALUATION OF DATA1. Analytical Method• Must be validated foraccuracy, precision, sensitivity, & specificity.• Using more than one analytical method for a study isnot valid—different methods may yield diff. results.• Data presented in both tabulated and graphic formfor evaluation.• Plasma drug concentration–time curve should beavailable.21
  • 22. EVALUATION OF DATA2. Pharmacokinetic Evaluation of the Data• Area under the curve to the last quantifiableconcentration (AUC0–t)• Area under the curve to infinity (AUC0–∞)• T max• C max• elimination rate constant, k• elimination half-life, t 1/222
  • 23. EVALUATION OF DATA3. Statistical Evaluation of the Data• (a) Analysis Of Variance (ANOVA) When p ≤ 0.05, the diff b/w 2 drug products is not“statistically significant”.• (b) Two One-Sided Tests Procedure Demonstrate if bioavailability of the drug from Testformulation is too low or high in comparison toreference drug. Evaluation of confidence limits—90% ± 20%23
  • 24. Waivers of In Vivo Bioequivalence Studies• Done when 2 drug products are: In same dosage form. Proportionally similar in active & inactive ingredients. Differ only in strengths of the medication.• Bioequivalence study of lower strength(s) can bewaived.• Only in vitro dissolution test is required to establishbioequivalency.24
  • 25. REFERENCES• Shargel. L, Applied Biopharmaceutics andPharmacokinetics, 5th edition, Mc GrawHill, Singapore, 2005, pp 460-475• Madan. P. L, Biopharmaceutics andPharmacokinetics, 1st edition, Jaypee, NewDelhi, 2000, pp 141-155• Chatwal. G. R, Biopharmaceutics andPharmacokinetics, 1st edition, Himalaya, newDelhi, 2003, pp 201-215• Brahmankar. D. M, Biopharmaceutics andPharmacokinetics—A Treatise, 1st editon, VallabhPrakashan, 2006, pp290-296 25
  • 26. 26THANK YOU