logging in or signing up BABE concepts 1 2008 goutham.atla Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 433 Category: Science & Tech.. License: All Rights Reserved Like it (1) Dislike it (0) Added: March 05, 2011 This Presentation is Public Favorites: 1 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript Bioavailability and Bioequivalence: General concepts and overview: Bioavailability and Bioequivalence: General concepts and overview Dr. Suresh Bandari M.Pharm Ph.D.Slide 2: WHAT IS IT??? HOW IS IT??? WHY IS IT??? REGULATION VERSUS PHARMACEUTICAL COMP.Facts: Facts Generic drugs are safe and effective alternatives to brand name prescriptions Generic drugs can help both consumers and the government reduce the cost of prescription drugsNDA vs. ANDA Review Process: NDA vs. ANDA Review Process Original Drug NDA Requirements Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies (Bioavailability/Bioequivalence) Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence Study (In Vivo, In vitro) Note: Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness . Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the original; drug).Generic Drug: Definition: Generic Drug: Definition Same active ingredient (s) Same route of administration Same dosage form Same strength Same indications Compares to reference listed drug (RLD)Bioavailability: Bioavailability The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation (quantifies ABSORPTION = ?, Reasons for poor F) Pharmacokinetics conc. vs time Conc.(mg/L) Time (h) 0 25 0.0 intravenous administration = 100% bioavailability AUC C max T maxSlide 7: Important Pharmacokinetic Parameters AUC: area under the concentration-time curve measure of the extent of bioavailability C max : the observed maximum concentration of drug measure of both the rate of absorption and the extent of bioavailability t max : the time after administration of drug at which C max is observed measure of the rate of absorptionSlide 8: The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect. Dissolution Absorption Survive metabolism Why do we care about BIOAVAILABILITY ?Slide 9: May have a drug with very low bioavailability Dosage form or drug may not dissolve readily Drug may not be readily pass across biological membranes (i.e. be absorbed) Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver) Important component of overall variability Variable bioavailability may produce variable exposureSlide 10: Extent of absorption is reflected by AUC , Rate of absorption, ka, is reflected by Tmax , Both Rate and Extent of absorption affect Cmax Leads to 4 possible relative scenarios: (R) Rapid, (E) Complete Absorption yields a short Tmax, high Cmax, high AUC (R) Rapid, (E) incomplete absorption yields a short Tmax, low Cmax, low AUC (R) Slow, (E) complete absorption yields a long Tmax, high Cmax, high AUC (R) Slow, (E) incomplete absorption yields a long Tmax, low Cmax, low AUC Rate versus Extent of AbsorptionSlide 11: Bioavailability Absolute bioavailability (F): Relative bioavailability ( F rel )Slide 12: Bioavailability: Same Dose Absolute bioavailability (F): Relative bioavailability ( F rel )Slide 13: Pharmaceutical Equivalents contain the same amount of the same active substance in the same dosage form meet the same or comparable standards intended to be administered by the same route Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalencePharmaceutical Equivalents: Pharmaceutical Equivalents Possible Differences Drug particle size Excipients Manufacturing Equipment or Process Site of manufacture Test Reference Could lead to differences in product performance in vivo Possible BioinequivalenceBioequivalence (BE): Definition: Bioequivalence (BE): Definition “ 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 .” CDER U.S. Food & Drug Administration Two products are bioequivalent if they are pharmaceutically equivalent bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the sameBioequivalence: BioequivalenceGoals of BE: Goals of BE Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product. Important for post-approval changes in the marketed drug formulationSlide 18: Why do we need Bioequivalence studies? No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety. With data to support similar in vivo performance (=Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.Slide 19: Two products are therapeutically equivalent if pharmaceutically equivalent their effects, with respect to both efficacy and safety, will be essentially the same as derived from appropriate studies bioequivalence studies pharmacodynamic studies clinical studies in vitro studies Therapeutic equivalenceSlide 20: Interchangeable pharmaceutical products If a product is demonstrated to be therapeutically equivalent to a reference product, then the products are considered interchangeable .Bioavailability for new/approved drugs : Bioavailability for new/approved drugs To establish essential pharmacokinetics such as rate of absorption, extent of absorption, rate of excretion and metabolism and elimination half life Bioavailability studies are also conducted to understand the influence of excipients, manufacturing procedures, patient related factors To develop new dosage form or to improve existing DFAssessment of bioavailability: Assessment of bioavailability Pharmacokinetic methods (indirect methods) Plasma data (i) Tp (ii) Cmax (iii) AUC Urine data (i) dXu/dt (Rate of drug excretion) (ii) Xu- ∞ (Cummulative drug excreted) (iii) Tu- ∞ (time for max. urinary excretion) Pharmacodynamic methods (direct methods) Acute pharmacological effect Clinical responseBioavailability study protocol: Bioavailability study protocol Title Principal investigator Project/protocol number and date Study objective Study design Experimental design Drug products Test products Reference product Dosage regimen Sample collection schedule Housing/confinementSlide 24: Fasting and meals schedule Analytical methods Study population Subjects Subject selection Medical history Physical examination Laboratory tests Inclusion/Exclusion criteria Restrictions/prohibitions Clinical procedures Dosage and drug administration Biological sampling schedule and handling procedures Activity of subjectsSlide 25: Ethical considerations Basic principles Institutional review board Informed consent Indications for subject withdrawal Adverse reactions and emergency procedures Facilities Data analysis Analytical validation procedure Statistical treatment of data Drug Accountability AppendixStudy Design: Basic design consideration: Study Design: Basic design consideration Minimize variability not attributable to formulations Minimize bias To compare performance of two products!!!Types of designs: Types of designs Parallel design Crossover design In parallel design products are randomly administered to the volunteers Disadvantage is inter subject variabilityCross over design: Cross over design Latin square crossover design Balanced incomplete block design In Latin square design each subject receives each formulation once Each formulation is administered once in each study periodAdvantages: Advantages Minimizes inter subject variability as each subject acts as his or her own control. Minimizes time effects on bioavailability as each formulation is administered in each study period Requires less number of volunteers for meaningful resultsDisadvantages: Disadvantages Longer time period to complete study because of washout period Completion of study depends on number of formulations to be tested Increased study period leads to high subject dropouts Ethical committee does not allow many trails on a subject for longer periodBalanced Incomplete Block Design: Balanced Incomplete Block Design Each subject receives not more than two formulations Each formulation administered same number of times Each pair of formulations occur together in the same number of subjectsSlide 32: Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed Alternative Single-dose, parallel, fasted (Long half-life) Amiodarone, Etidronate Single-dose, replicate design (Highly Variable Drugs) Multiple-dose, two-way crossover, fasted (Less Sensitive, non-linear kinetic) Clozapine Clinical endpoint study (topicals, nasal suspensions) Parallel or crossover?, Fasted or Fed?, Single or Multiple?, Replicate or nonreplicate?Slide 33: Washout period Duration of washout period for cross-over design should be approximately > 5 times the plasma apparent terminal half-life However, should be adjusted accordingly for drugs with complex kinetic model Single or multiple dose studies For BE studies (relative bioavailability) single dose studies may be needed (Analgesics) Multiple dose studies for Time released products, enteric coated products etc.“Rule of Five”: “Rule of Five” 5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body 1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875%Test products : Test products Evaluated to select best dosage form of new drug or existing drug among different DF To select best formulation of new drug or existing drug from different formulations To carry Bio equivalence studies Reference Product Innovators product (FDA approved)Bioanalytical Method Validation: Bioanalytical Method Validation Quantitative determinations of drugs in biological samples, such as blood or plasma, play a significant role in evaluation and interpretation of bioequivalence data. Essential to use a well-characterised and fully validated analytical method to yield reliable results.Bioanalytical Method Validation: Bioanalytical Method Validation Method Validation should include Accuracy Precision Sensitivity Specificity Recovery StabilityBioanalytical Method Validation: Accuracy Closeness of determined value to the true Value The acceptance criteria is mean value < 15% deviation from the true value. At LOQ, 20% deviation is acceptable Bioanalytical Method ValidationBioanalytical Method Validation: Precision The closeness of replicate determinations of a sample by an assay The acceptance criteria is < 15% CV, at 20% LOQ Sensitivity The limit of quantitation is the lowest concentration which can be measured with acceptable accuracy and precision Bioanalytical Method ValidationBioanalytical Method Validation: Selectivity Ability of the method to measure only what it is intended to measure in the presence of other components in the sample. Blank samples of the biological matrix should be tested for the interfering peak. Bioanalytical Method ValidationBioanalytical Method Validation: Recovery The extraction efficiency of an analytical process, reported as an percentage of the known amount of an analyte. Recovery does not have to be 100% but the extent of recovery of internal standard and analyte should be consistent. Stability During, sample collection , sample storage and sample analysis process, the stability of drug in matrix should be conducted Bioanalytical Method ValidationTypical HPLC chromatograms of Fenoverine in human serum (blank, Sample & Standard): Typical HPLC chromatograms of Fenoverine in human serum (blank, Sample & Standard)Subjects: Subjects Healthy subjects Vs Patients Healthy subjects avoid variations Complications with patients may be Difficult to obtain may patients at given place Severity of disease varies in patient Ethical considerations may not permit Treatment involves use of several drugs simultaneouslyEthical considerations : Ethical considerations Basic principles Institutional review board Informed consent Indications for subject withdrawal Adverse reactions and emergency proceduresPlasma data: Plasma data Basic assumption is bioequivalent products produce super imposable plasma level – time curves Time of peak plasma concentration (tp) – indicates rate of drug absorption At tp, rate of drug absorption is equal to rate of drug elimination Units of tp are hr or min. Peak plasma concentration (Cmax) – indicates maximum drug concentration, shows whether drug is in therapeutic range or not Units of Cmax are mcg/ml or ng/mlSlide 46: AUC represents extent of absorption or fraction of dose that reaches systemic circulation AUC 0-∞ is sum of AUC 0-t and AUC t- ∞ where t is last time point of plasma sample collection. AUC 0-t is calculated by Trapezoidal method and AUC t- ∞ is obtained by equation C*/K, C* is concentration of drug in last plasma sample, K is overall elimination rate constant. AUC is independent of route of administration, Units are concentration-time/volume. (ng-h/ml)Urine studies: Urine studies It involves non invasive method of sampling Concentration of drug in urine is greater than blood and easy to estimate Amount of drug excreted is obtained directly Drug should be eliminated unchanged in the urine Limitations Difficult to estimate absorption rate of rapidly absorbing drug Metabolites may be eliminated in urine and estimation may be difficultUrine data: Urine data This is based on observation that rate of urinary excretion of a drug is directly proportional to concentration of drug in blood. Urine samples must be collected for atleast 7 half lives Avg. rate of drug excretion in urine (dXu/dt) Generally follows first order, depends on blood concentration. The plot of dXu/dt vs time at mid point of urine collection is a mirror image of plasma - time plotSlide 49: Bioavailability: The rate and extent to which the parent compound reaches the general circulation. Absolute Bioavailability requires I.V. administration Ratio of the oral:intravenous AUC values normalized for dose F abs = (AUC oral / AUC iv )*(Dose iv / Dose oral ) Relative Bioavailability no I.V. reference comparison AUC values (ratio) of different dosage forms / formulations F rel = (AUC a / AUC b ) * (Dose b /Dose a ) Bioavailability and Its AssessmentSlide 50: 20 mg administered as an i.v. bolus (Diovan) 80 mg given as a solution and a capsule (Diovan)Rate of urinary excretion of drug vs time plot: Rate of urinary excretion of drug vs time plot A Rate of urinary excretion Time (h) 0 25 0.0 B Max. rate of Excretion CSlide 52: Cummulative amount of drug excreted in urine in infinite time, this is directly related to the amount of drug absorbed Absolute bioavailability (F): Relative bioavailability ( F rel )Slide 53: Time for max. urinary excretion, It is time required for the absorption and complete elimination of drug. It is the measure of both rate and extent of drug absorption from drug product. Pharmacodynamic Methods Acute pharmacological effect Established dose response curve Easily measurable pharmacological responseScheme of Oral Dosage Form : Scheme of Oral Dosage Form Human Intestinal Absorption ( HIA ) Oral Bioavailability (% F ) 1,2 – Stability + Solubility 3 – Passive + Active Tr. 4 – Pgp efflux + CYP 3A4Clinical/PD Dose-Response: Clinical/PD Dose-Response Bioequivalence studies assess in vivo impact of changes to the dosage form/process after pivotal studies commence to ensure product on the market is comparable to that upon which the efficacy is based Theophylline Concentration[mg/L] FEV 1 (% normal) Mitenko & Ogilvie NEJM 289:600-3, 1973Slide 56: FDA Draft-Guidance for Industry (1997) Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products New Dosage Form of a Previously Studied Drug In some cases, modified release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form from a previously studied immediate-release dosage form. Because the pharmacokinetic patterns of controlled-release and immediate release dosage forms are not identical, it is generally important to have some understanding of the relationship of blood concentration to response to extrapolate to the new dosage form.Slide 57: Why do we need Bioequivalence studies? No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety. With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.Approaches to Determining BE (21 CFR 320.24): Approaches to Determining BE (21 CFR 320.24) In vivo measurement of active moiety in biologic fluid In vivo pharmacodynamic comparison (Topical Corticosteroid) In vivo clinical comparison (Nasal suspensions) In vitro comparison (Nasal Solution, Topical solution, Oral solution)Study Design: Basic design consideration: Study Design: Basic design consideration Minimize variability not attributable to formulations Minimize bias To compare performance of two products!!!Study Designs: Study Designs Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed Alternative Single-dose, parallel, fasted (Long half-life) Amiodarone, Etidronate Single-dose, replicate design (Highly Variable Drugs) Multiple-dose, two-way crossover, fasted (Less Sensitive, non-linear kinetic) Clozapine Clinical endpoint study (topicals, nasal suspensions) Parallel or crossover?, Fasted or Fed?, Single or Multiple?, Replicate or nonreplicate?Study Designs: Duration of washout period for cross-over design should be approximately > 5 times the plasma apparent terminal half-life However, should be adjusted accordingly for drugs with complex kinetic model Study Designs“Rule of Five”: “Rule of Five” 5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body 1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875%Study Designs: Sample size determination significant level ( α = 0.05) 20% deviation from the reference product power > 80% Sample time determination adequate data points around t max 3 or more time of t 1/2 to around AUC 0-t = at least 80% AUC 0-inf Study DesignsStudy Designs: Subjects? (Inclusion/exclusion criteria) LABEL Study Designs (such as…) Healthy subjects (male and female) 18-55 years old, BMI = 18 – 25 kg/m2 Non-smokers/without a history of alcohol or drug abuse Medical history/Clinical Lab test values must be within normal ranges Contraindication Refrain from the concomitants use of any medications or food interact with GI, renal, liver function from 28 days prior study Day1 through the safety follow up-visit.Study Design: Case 1: Study Design: Case 1 Please conduct BE study of two brands of drug A in Tablet Information? PK information half-life = 10 hrs Low within subjects variability =~ 10-15% Drug mechanismsStatistical Analysis (Two one-sided Tests Procedure): Statistical Analysis (Two one-sided Tests Procedure) AUC (Extent) and C max (Rate) – Log transformation - 90% Confidence Intervals (CI) of the difference in Log (AUC t ) –Log (AUC R ) must fit between 80%-125%Statistical Analysis 80%-125%: Statistical Analysis 80%-125% What does this mean? Can there be a 46% difference? What is a point estimate? What is a confidence interval?Statistical analysis: Statistical analysis BE criteria -Two one-sides tests procedure Test (T) is not significantly less than reference Reference (R) is not significantly less than test Significant difference is 20% ( α = 0.05 significance level) T/R = 80/100 = 80%, or 100/80 =125%BE Results (90% CI): BE Results (90% CI) T/R (%) 80% 125% Demonstrate BE Fail to Demonstrate BE Fail to Demonstrate BIE Demonstrate BIE Demonstrate BIEProblems of 2×2 Crossover Design: Problems of 2×2 Crossover Design Overparameterization Carry-over effect is confounded If carryover effect exists, the drug effect cannot be estimated correctlySlide 71: Screening of Volunteers Clinical Chemistry Clinical Research Implementation of QUALITY SYSTEMS Bioanalytical Project Management Technology Services Pharmacokinetics & Biostatistics Quality Assurance How to insured?In vivo BE Inspections: In vivo BE Inspections Covers clinical and analytical components Study design Issues Analytical methodThank you and Questions??: Thank you and Questions??Back up slides: Back up slidesStatistical Method: Case 1: Statistical Method: Case 1Study Design: Case 1: Crossover Design 2x2 Crossover design A single-dose bioequivalence study is performed in normal, healthy, adult volunteers. 18 subjects are hired (Male or Female?) . The subjects are randomly selected for each group and the sequence of drug administration is randomly assigned. One-week washout periods Fasted or Fed? Study Design: Case 1Slide 78: Pharmacokinetics “what the body does to the drug” Absorption Distribution Metabolism Elimination Pharmacodynamics “what the drug does to the body” wanted effects - efficacy unwanted effects - toxicity dispositionSlide 79: Dose regimen Response Exposure Site of action Pharmacokinetics PharmacodynamicsSlide 80: Basic Pharmacokinetic Concepts Bioavailability Definition How absorption affects bioavailability? Food Effect How drug metabolism affects bioavailability? How transporters affect bioavailability? Bioequivalence Definition Bio-IND Waivers of In Vivo Study Requirements Biopharmaceutics Classification System (BCS) General OutlineSlide 81: Basic Concepts Easy to understand using intravenous route No absorption phase Simple to follow Concepts clear with less assumptions Need some math background algebra, log scale, Simple linear Equations etc complex math (differential equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc. Drug Product Drug in Blood Distribution to Tissue and Receptor sites Metabolism ExcretionIV administration, contd.,: IV administration, contd., Following dose administration, we need to follow its drug’s disposition to understand its PK characteristics. This is achieved by analyzing the changes of the drug and/or its metabolite(s) in blood, plasma, urine etc. A simple approach is to generate Drug Concentration-Time profile Dosing Sampling at Pre-determined Time intervals Bio-analytics Conc. vs time profiles Blood withdrawalConcentration versus Time Profiles: Concentration versus Time Profiles One-Compartment Model Assumes body as one compartment 1 Two-Compartment Model Central compartment (drug entry and elimination) Tissue compartment (drug distributes) 1 2 k k Dose Dose Broadly the concentration – time profiles can be viewed as two different waysSlide 84: The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues. The distribution phase for amino glycosides is only 15-30 minutes, therefore, we can use a one-compartment model with a high degree of accuracySlide 85: Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model Vancomycin is the classic example, it's distribution phase is 1 to 2 hours. Therefore, the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model . You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.