Bioequivalence and Generic Substitution PharmSci2 Lecture G PDF

Bioequivalence and Generic Substitution 1  Learning Objectives At the end of this lecture and the associated tutorial you should know and understand: What “generic medicines” are What “bioequivalence” means How bioequivalence is established How “generic substitution” o...

Bioequivalence and Generic Substitution 1  Learning Objectives At the end of this lecture and the associated tutorial you should know and understand: What “generic medicines” are What “bioequivalence” means How bioequivalence is established How “generic substitution” operates Some significant issues with generic medicines and generic substitution 2  Outline 1. 1. Generic Medicines 2. 2. Drug disposition form solid oral dosage forms 3. 3. Bioavailability and Bioequivalence 4. 4. Generic Substitution 3  1. Generic Medicines Same drug and potency as originator brand Same dose form Same drug release characteristics Same clinical efficacy and safety Same stringent regulatory controls on manufacture and quality control Generic cheaper because manufacturer does not carry the massive costs of development and clinical testing 4 2. Drug disposition from solid oral dosage forms 1. Ingestion 2. Disintegration → Suspension 3. Dissolution of active ingredient 4. Absorption 5. First pass through gut wall and liver 6. Metabolism 7. Distribution 8. Pharmacological effects 9. Elimination 5  Drug concentration in plasma after oral administration Kel , t1/2 Image 6 from: https://lh4.googleusercontent.com/cubm6O_Ki9MZNi1vm56AnHsmBUmYJWXtoxL8cxzrDZohRUfozzEdOJ57mhDnrGq42iNYh- 9rXVyKuUmHIOtvSB09vT-HEHhsIO_kQOVxEPEYJnbdcCUZ0Iq91HyHY4ZAYRadEKGH  Plasma Concentration of Drug Absorption 80 Cmax, Tmax 60 Concentration Distribution 40 20 Elimination AUC kel t1/2 0 0 4 8 12 16 20 24 Hours 7 Calculation of Area Under the Curve (AUC) Image from: https://www.certara.com/2014/02/24/extrapolating-auc-to-infinity/? 8  AUC using the Trapezoidal Rule Image from: https://www.sciencedirect.com/topics/nursing-and-health-professions/area-under-the-moment-curve 9 Pharmacokinetic parameters used in single dose bioequivalence studies Tmax Cmax kel = Ln(2) / t1/2 t1/2 = Ln(2) / kel AUCt AUC = AUCt + Clast / kel 10 Plasma concentration after multiple dosing with a drug that accumulates Cmax, Tmax Cmin 11 Image from: https://www.boomer.org Pharmacokinetic parameters used in multiple dose bioequivalence studies At “steady state” Tmax Cmax Cmin PTF* AUCτ τ** *PTF = peak trough fluctuation = {Cmax - Cmin} / Cmax **τ = dose interval 12  2. Bioavailability and Bioequivalence Bioavailability is a measure of the rate and extent of absorption of the active form (or forms) of a drug substance from a medicine into the systemic circulation. The active form may be a metabolite. Bioequivalence: Two medicinal products are considered to be bioequivalent if the rates and extents to which the active form or forms of the drug substance reach the systemic circulation from the two products are so closely comparable that their therapeutic efficacy and safety can be expected to be essentially the same. 13  Factors affecting bioavailability Physicochemical properties of the active ingredient(s) Dose form and formulation Excipients First pass metabolism State of the stomach and intestines Gastrointestinal motility Effects of food and beverages Effects of other drugs 14  Bioequivalence Plasma Concentration of Drug 80 Product A 60 Concentration Product B 40 20 0 0 4 8 12 16 20 24 Hours 15  Design of typical comparative bioavailability study Study type – usually 2-way crossover; sometimes parallel – usually single dose; multiple dose for sustained release product or if drug accumulates Typically 20-30 volunteers Usually healthy, normal weights, 18-55yrs Fasted or non-fasted Dose safe for healthy volunteers Blood sampling times selected to characterise plasma curve and PK parameters adequately Measurement of active entities (unchanged drug/active metabolites) in plasma 16  2-Way crossover study design Period 1: Period 2: Group 1: Reference Test (washout) Group 2: Test Reference 17  Conduct of bioequivalence study 1. Enrolment and screening of volunteers 2. Standardisation of conditions 3. Dosage and sampling (Period 1) 4. Dosage and sampling (Period 2) 5. Assay of drug and/or metabolites in plasma samples 6. Pharmacokinetic calculations 7. Statistical analysis of data 8. Preparation of report 18  Distribution of measurement data Many scientific measurements (e.g. results of quantitative chemical analysis) and biological measures (e.g. height, IQ) are distributed according to a “normal” symmetrical bell-shaped curve with a mean  (mu) and a standard deviation  (sigma) specific to that “population”. 19  A  B 2 2 If we know that an individual value “x” comes from a normal distribution with mean  and standard deviation , we may not know the values of  or , but we can be 95% confident that x lies between A ( - 2) and B ( + 2). That is the same as saying  is not less than 2 below x and not more than 2 above x. Hence, 95% confidence interval for  is (x - 2) to (x + 2) 20  Estimating the population mean from a sample mean We cannot get  or  from a single value drawn randomly from the population. However, if we take a sample of n randomly selected individuals from the population and determine the mean “m” and standard deviation “s” for that sample we can get an estimate and a confidence interval for . 21 Sample means follow a “t-distribution” curve centred on  and with a width determined by “s” and the “degrees of freedom” df = n-1. The t-distribution curve is shorter and broader than the normal distribution curve, but becomes the same if n  250. 22 23 What does a 90% confidence interval mean? A 90% confidence interval, for example, means that if we took a lot of samples of n and calculated the 90% CIs for each of them we would find that the true population mean  (if we knew its value) would lie somewhere inside 90% of those confidence intervals and outside 10% of them. Thus, if we only take one sample and calculate its 90% CI, we can be 90% confident that the population mean lies somewhere within that calculated interval. 24  Distribution of pharmacokinetic data Numerous pharmacokinetic studies have demonstrated that Tmax, Cmax, Cmin, AUC, and t1/2 follow a “log-normal” distribution (bell-shaped curve skewed to the right) rather than a symmetrical normal distribution. If the data are converted to their logarithms (base 10 or base e) the results follow a normal distribution. We can therefore use statistical analyses based on normal distribution equations if we first convert the data to logarithms, then do the statistical analyses of the logarithms, and finally convert the results back to real numbers. 25 Normal and Log-normal Distributions Normal Lognormal 26  Standard Statistical Analyses (all done using a computer!) Mean, standard deviation, range Tmax [discrete variable] – Estimate and 90% “non-parametric” confidence interval for median difference (trial - reference) Cmax, AUC, etc. [continuous variables, lognormal distribution] – Log-transformation of data – Analysis of variance (ANOVA) – Estimates and 90% confidence intervals for log of geometric mean ratios (trial/reference) – Conversion back to real numbers 27  Normal criteria for bioequivalence Test product pharmaceutically equivalent to comparator Difference in Tmax within clinically relevant limits 90% Confidence Intervals for Cmax, AUC, (Cmin and PTF) ratios fit completely within the range 80% - 125% [i.e. differences ≤ 20% in either direction] A difference of ± 20% is less than the usual dose-to- dose variation and is not considered to be clinically detectable or significant. 28 90% Confidence Intervals and Bioequivalence Image from: https://bpac.org.nz/bpj/2009/generics/img/testing-chart.jpg 29  Ratios: Cmax 102% (90% CI: 100-104%) AUC 99% (90% CI: 97-102%) Mean plasma concentrations of ciprofloxacin at different time intervals after single oral administration of 250-mg tablet of Ciproxin and Quinox to 24 healthy male volunteers. (Ref: M. A. K. Azad, et al, J Applied Research Vol 7, No. 2, 2007, 150-7) 30 Image from: https://bpac.org.nz/bpj/2009/generics/img/testing-chart.jpg Example of non-equivalent products 90% CI for Budeprion XL vs. Wellbutrin XL: Cmax = 65-87%; AUC = 77-96% Image source: https://www.nejm.org/doi/full/10.1056/NEJMp1212969 31  Importance of bioequivalence Majority of prescription medicines are oral dose forms Adequate and consistent bioavailability is vital Innovator medicines: – Market vs. clinical trial formulations – 60-70% not identical, but bioequivalent New salts and prodrugs – Bioequivalent with respect to active moiety Generic medicines: – Generic vs. innovator product 32 4. Generic substitution Substitutable if proven to be bioequivalent and listed as bioequivalent in the Schedule of Pharmaceutical Benefits (PBS) Not substitutable if not proven to be bioequivalent 33 Generic/Innovator ratios AUC Mean ratio 100-102%, SD 3.5% 67% within ± 1 SD 95% within ± 2 SD (7%) of each other 99% within ± 2.6 SD (9%) of each other Cmax Mean ratio 101-102%, SD 4.5% 95% within ± 2 SD (9%) of each other 99% within ± 2 SDS (12%) of each other 34  Generic vs. Generic: Cmax Estimated ratios and differences Mean ratio GenA / GenB = 100% Std Dev = 4.5 x √2 = 6.4% 95% within ± 13% of each other 99% within ± 17% of each other 35  Generic vs. Generic: AUC Estimated ratios and differences Mean ratio GenA / GenB = 100% Std Dev = 3.5 x √2 = 5% 95% within ± 10% of each other 99% within ± 13% of each other 36 Basis of Generic Substitution  BE  Generic A Innovator Product BE  BE  Generic B 37  Generic Substitution in Practice Risk elimination vs. risk management Theoretical risk vs. actual experience Long history of success for most drugs Significant problems rare and idiosyncratic: – Disease progression – Inadequate dose titration – Sensitivity to different excipients – Patient bias or perception – Confusion and double dosing Substitution is at discretion of prescriber and/or patient 38 Doctor’s prescription includes a box to tick if brand substitution is not permitted Otherwise, brand substitution is permitted if patient agrees Image from: https://www.humanservices.gov.au/sites/ 39 default/files/images/pbs-prescription.png  Summary (1) Bioavailability is a measure of the rate and extent of absorption of the active form (or forms) of a drug substance from a medicine into the systemic circulation. The active form may be a metabolite. Bioequivalence: Two medicinal products are considered to be bioequivalent if the rates and extents to which the active form or forms of the drug substance reach the systemic circulation from the two products are so closely comparable that their therapeutic efficacy and safety can be expected to be essentially the same. 40  Summary (2) Bioequivalence is tested by dosing volunteers with the generic medicine (test product) and the corresponding innovator (reference) product, measuring blood levels, calculating the individual and average pharmacokinetic parameters (Tmax, Cmax, AUC, etc) for the two products, and subjecting the data to statistical analysis to determine if there is any clinically significant difference between the products 41  Summary (3) The normal criteria for concluding bioequivalence are: The test product is pharmaceutically equivalent to comparator Difference in Tmax is within clinically relevant limits The 90% Confidence Intervals for Cmax, AUC, (Cmin and PTF) ratios (Test/Ref) are within the range 80% - 125% [i.e. differences ≤ 20% in either direction. A difference of ± 20% is less than the usual dose-to-dose variation and is not considered to be clinically detectable or significant.] 42  Summary (4) Oral dose forms are only interchangeable if they are bioequivalent. Interchangeability is at the discretion of the prescriber AND the patient (not the pharmacist!) Significant problems with generic substitution are rare, idiosyncratic, and may be due to: – Disease progression – Inadequate dose titration – Sensitivity to different excipients – Patient bias or perception – Confusion and double dosing 43