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1 The Role of Bioavailability in Pharmaceutical Product Development Alwyn Pidgen November 2012.

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1 1 The Role of Bioavailability in Pharmaceutical Product Development Alwyn Pidgen November 2012

2 2 Absolute bioavailability  Is the fraction (F) of unchanged drug absorbed following extravascular administration when compared to an intravenous dose.  The intravenous dose is assumed to be completely available  F can be expressed as either a decimal fraction (e.g. 0.8) or as a percentage (e.g. 80%) F(abs) = AUC(ev) * Dose(iv) AUC(iv) Dose(ev) AUC(iv) Dose(ev)

3 3 Relative bioavailability  Compares the impact of different dosage forms, different routes of administration and different dosing conditions on drug absorption.  Examples include: - Capsule v Tablet, Oral v Rectal, Day time v Night time dosing, Immediate release v Modified release. F(rel) = AUC(test) * Dose(ref) AUC(ref) Dose(test) AUC(ref) Dose(test)

4 4 Two medicinal products are called Pharmaceutical equivalents if they contain the same amount of the same active substance in the same dosage form, which meet comparable regulatory standardsof quality, purity and potency. Two medicinal products are called Pharmaceutical equivalents if they contain the same amount of the same active substance in the same dosage form, which meet comparable regulatory standards of quality, purity and potency. They may differ in characteristics such as excipients, shape, scoring and release mechanisms. Pharmaceutical equivalence

5 5 Bioequivalence Two medicinal products are classed as bioequivalent when their rate and extent of absorption meet strict regulatory requirements after administration of the same molar dose.

6 6  Particle size  Solubility (water and lipids)  Material polymorphism (Crystallisation)  Change in Manufacturing process HOWEVER - Pharmaceutical equivalence does not automatically assure bioequivalence mainly due to changes in dissolution, which can be influenced by: -

7 7 HOWEVER Since pharmacologic response is related to circulating drug concentrations – then:- Two pharmaceutically equivalent products that give rise to ‘equivalent’ concentrations of the active species in blood or plasma (viewed as a profile over time) will give equivalent therapeutic effects. KEY CONCEPT IN BIOEQUIVALENCE ‘Equal amounts of the same drug administered in equivalent products will show equal therapeutic effects’. A direct demonstration of therapeutic equivalence requires an expensive clinical (efficacy/safety) trial

8 8 Why perform Bioequivalence studies ?  To enable clinical trial formulations to be modified or production ‘scaled up’ throughout a drug’s development (NDA).  To compare a clinical trial formulation with the ‘to be marketed’ product just prior to filing (NDA).  To compare a generic drug product with a corresponding reference drug (ANDA).  For post- approval formulation changes undertaken by the ‘innovator’ company (NDA).

9 9 When are bioequivalence studies not normally needed ?  If the product differs only in the strength of the active substance it contains and the pharmacokinetics are linear  If the product has been slightly reformulated or the manufacturing method slightly modified by the original manufacturer in ways that can be argued to be irrelevant (using approved in-vitro tests)  If the product is to be administered parenterally as a solution and contains the same active substances and excipients as a medicinal product currently approved.

10 10  If the product is a liquid oral form in solution containing the active substance in the same concentration and form as a currently approved medicinal product  An acceptable correlation between dissolution rate in- vivo and in-vitro has been shown (FDA regulation).  Products intended for local use to act without systemic absorption

11 11  Healthy volunteers  Male subjects or women of non-child bearing potential  Aged between 18 and 55  Weight within accepted normal BMI values  Single dose.  2-period Crossover design Typical Study Design Features

12 12 Period Period 12 Subjects within Sequence 1 RT Subjects within Sequence 2 TR Crossover Design R = Reference and T = Test formulation  Ensures a within subject comparison – most efficient design.  A washout interval between periods ensures that all the active ingredient from the first treatment has been cleared from the body before administration of the second treatment.

13 13  Should be appropriately statistically powered if study is pivotal for filing  An estimate of a drug’s intrinsic (within subject) variability is obtained from previous studies or publications  Should not be smallerthan 12  Should not be smaller than 12 SAMPLE SIZE

14 14  The main active metabolite of an inactive pro-drug should be measured if the plasma levels of the parent are too low for accurate assay measurement. WHAT TO MEASURE  Plasma concentrations of the parent drug are generally recommended.  Parent drug is more sensitive to formulation changes than any (subsequently formed) metabolite.

15 15 Enantiomers versus Racemates  Measurement of the racemate is recommended.  Measurement of individual enantiomers is only recommended if they have different PK or PD characteristics Fixed combinations Separate analyses are performed for each active substance when assessing the Bioequivalence of the fixed combination product versus co- administration of the individual products.

16 16 Peak exposure (C max ) Important parameter - may be linked to safety and/or efficacy. PHARMACOKINETIC PARAMETERS Early exposure Only consider if previous clinical studies indicate that rapid release is linked to adverse events. Parameters may include AUC( 0–tmax ) and t max tmax

17 17 Parameters  AUC to the last measurable time point (AUC 0-t )  AUC extrapolated to infinite time (AUC 0-inf )  AUC truncated at 72h (AUC 0-72 ) – (long half-life drugs only) Other considerations oThe elimination rate constant (k el ) and terminal half-life (t 1/2 ) should be reported - particularly if AUC( 0-inf ) is used. Total exposure (AUC) Generally, the most important BE parameter since AUC is directly proportional to the amount of drug absorbed.

18 18 STATISTICAL ANALYSIS Calculate 90% confidence intervals (CI) of the ratio of the treatment means (test/reference) for Cmax, and AUC. Log transformed data prior to analysis. If statistical evaluation of tmax is required then a non- parametric significance test is performed on the untransformed data.

19 19 90%confidence 5% risk lower limit % confidence interval for BE upper limit 1.25 TTTT RRRR 0.8 ≤  test  ref ≤ 1.25

20 20 tmax : Only consider if clinically relevant rapid release is claimed and/or onset of action is related to adverse events. AUC : 90% CI for test treatment to be within ≥ 0.8 and ≤1.25 of the reference treatment (FDA and EMEA) AUC : 90% CI for test treatment to be within ≥ 0.8 and ≤ 1.25 of the reference treatment (FDA and EMEA) Range to be tightened in the case of a drug with a narrow therapeutic window (e.g. digoxin, phenytoin) (FDA and EMEA). This may also be applicable to Cmax. Cmax : 90% CI for test treatment to be within ≥ 0.8 and ≤1.25 of the reference treatment(FDA and EMEA) Cmax : 90% CI for test treatment to be within ≥ 0.8 and ≤ 1.25 of the reference treatment (FDA and EMEA) A wider interval may be clinically acceptable (see guidelines). Within-subject variability (%CV) for Cmaxis generally higherthan AUC. Cmax is also highly dependent upon sampling times. A wider interval may be clinically acceptable (see guidelines). Within-subject variability (%CV) for Cmax is generally higher than AUC. Cmax is also highly dependent upon sampling times. The Regulatory acceptance criteria

21 21  Propafenone – anti-arrhythmic drug  Undergoes extensive first-pass metabolism  Wide range of half-life  Bioequivalence study undertaken  Apotex (Generic) v Rhythmol (Reference)  300mg tablet  18 healthy subjects  2-way crossover An example  ‘Highly Variable Drugs:Experience with Propafenone’ -Yu Chung Tsang, Radu Pop & Michael Spino

22 22 Mean Plasma concentrations

23 23 Individual variability

24 24 PK parameters Statistical analysis (CV = SD/Mean) Apotex is not Bioequivalent to Rhythmol

25 25 Reasons for BE failure  Very high inter-subject CV for Cmax & AUC  High intra-subject variability (46%) from ANOVA  Propafenone falls into the category of a ‘highly variable drug’ – hence sample size used was inadequate.  Variability in elimination characteristics due to the metabolism of propafenone being influenced by genetics ot 1/2 (fast metabolisers) = 2-10h ot 1/2 (slow metabolisers) = 10-32h oDrug levels 5 times higher in slow metabolisers

26 26 BIOLOGICAL PRODUCTS

27 27  They are subject to a lengthy approval process which requires substantial additional data compared to chemical generics.  Biosimilars describe officially-approved versions of innovator biological products made by a different sponsor following patent expiry.  Biological products are generally derived from living material - human, animal, or micro-organism - are complex in structure and can be difficult to replicate.  Biological products are generally derived from living material - human, animal, or micro-organism - are complex in structure and can be difficult to replicate.  Unlike the more common small-molecule drugs, biologics can be sensitive to changes in manufacturing processes and copies may perform differently than the original branded product

28 28 Regulatory guidance  EMEA guidance available since several ‘similar medical products’ approved under this process.  Growth hormone (Omnitrope – Sandoz)  Erythropoietin (Abseamed – Medice Arzneimittel Putter)  Granulocyte-Colony Stimulating Factor (Tevagrastim – Teva Generics)  FDA used a similar approval process to the EMEA for Biosimilars - but decided new legislation was needed. This was passed in 2010 – still awaiting new approvals under this process.

29 29  Abseamed is an injectable solution (i.v. or s.c.) to treat anaemia in patients with chronic renal failure or patients on chemotherapy.  The reference product Eprex containsepoetin alfa which is a man-made version of Erythropoietin (EPO).  The reference product Eprex contains epoetin alfa which is a man-made version of Erythropoietin (EPO).  EPO is produced naturally in the body mostly by the kidneys. It stimulates the bone marrow to produce red blood cells.  When the body does not produce enough EPO - severe anaemia can occur. Epoetin alfa is then administered to provide the necessary stimulus to the bone marrow. EMEA approval for Abseamed

30 30 Non-Clinical studies undertaken PK and PD  In vitro – receptor binding cell proliferation  In-vivo- 5 day PK and PD study in dog Toxicology  Repeat dose - 13 weeks in dog  2 rabbit studies – various routes of administration  Immunogenicity in dog and rabbit

31 31 Clinical studies undertaken PK and PD  5 PD biomarker studies in healthy volunteers (n=234)  All PK parameters evaluated  Absolute Hb response, reticulocyte counts Efficacy  2 double blind randomised group parallel trials  Anaemia due to chronic renal failure (n=478)  Chemotherapy induced anaemia (n 114) Safety follow up  Patients included = 388  Duration = 1 year

32 32 FDA (www.fda.gov/cder/guidance/index.htm)  Bioavailability & Bioequivalence studies for orally administered drug products – general considerations – March 2003  Statistical approaches to establishing Bioequivalence – January 2001  Food-effect Bioavailability & Fed Bioequivalence studies – December 2002  Modified Release Solid Oral Dosage Forms - Scale-Up and Post-approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation – Sept 1997  Dissolution testing of Immediate release solid oral dosage forms - Aug 97  Extended release oral dosage forms : Development, Evaluation & Application of In-vitro/In-vivo correlations – Sept 97 EMEA (www.emea.europa.eu/index/indexh1.htm)  Guideline on the Investigation of Bioequivalence - January Doc. Ref.CPMP/EWP/QWP/1401/98  Note for guidance on quality of Modified Release products (A Oral dosage forms; B Transdermal dosage forms) – July 1999  Guideline on Similar Biological Medicinal Products– Nov 2004  Guideline on Similar Biological Medicinal Products – Nov 2004  Guideline on Similar Biological Medicinal Products containing Biotechnology- Derived proteins as active substance: Non-Clinical and Clinical issues – June 2005  Guideline on Similar Biological Medicinal Products containing Biotechnology- derived Proteins as active substance: Quality Issues – June 2005 Useful Regulatory Guidance documents


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