Presentation on theme: "Absolute bioavailability"— Presentation transcript:
1 The Role of Bioavailability in Pharmaceutical Product Development Alwyn Pidgen November 2012
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 availableF 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)
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)
4 Pharmaceutical equivalence 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.
5 BioequivalenceTwo 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 HOWEVER - Pharmaceutical equivalence does not automatically assure bioequivalence mainly due to changes in dissolution, which can be influenced by: -Particle sizeSolubility (water and lipids)Material polymorphism (Crystallisation)Change in Manufacturing process
7 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 HOWEVERSince 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.
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).For post- approval formulation changes undertaken by the ‘innovator’ company (NDA).To compare a generic drug product with a corresponding reference drug (ANDA).
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 linearIf 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 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 productAn 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 Typical Study Design Features Healthy volunteersMale subjects or women of non-child bearing potentialAged between 18 and 55Weight within accepted normal BMI valuesSingle dose.2-period Crossover design
12 Crossover DesignPeriod12Subjects within Sequence 1RTSubjects within Sequence 2R = Reference and T = Test formulationEnsures 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 SAMPLE SIZEShould be appropriately statistically powered if study is pivotal for filingAn estimate of a drug’s intrinsic (within subject) variability is obtained from previous studies or publicationsShould not be smaller than 12
14 Plasma concentrations of the parent drug are generally recommended. WHAT TO MEASUREPlasma concentrations of the parent drug are generally recommended.Parent drug is more sensitive to formulation changes than any (subsequently formed) metabolite.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.
15 Enantiomers versus Racemates Measurement of the racemate is recommended.Measurement of individual enantiomers is only recommended if they have different PK or PD characteristicsFixed combinationsSeparate analyses are performed for each active substance when assessing the Bioequivalence of the fixed combination product versus co- administration of the individual products.
16 PHARMACOKINETIC PARAMETERS Early exposureOnly consider if previous clinical studies indicate that rapid release is linked to adverse events.Parameters may include AUC(0–tmax)and tmaxtmaxPeak exposure (Cmax)Important parameter - may be linked to safety and/or efficacy.
17 AUC to the last measurable time point (AUC0-t) Total exposure (AUC)Generally, the most important BE parameter since AUC is directly proportional to the amount of drug absorbed.ParametersAUC to the last measurable time point (AUC0-t)AUC extrapolated to infinite time (AUC0-inf)AUC truncated at 72h (AUC0-72) – (long half-life drugs only)Other considerationsThe elimination rate constant (kel) and terminal half-life (t1/2) should be reported - particularly if AUC(0-inf) is used.
18 STATISTICAL ANALYSISCalculate 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 90% confidence interval for BE 5% risk5% risk90%confidenceTlower limit0.8upper limit1.25Rtest0.8 ≤≤ 1.25ref
20 The Regulatory acceptance criteria 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)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.tmax : Only consider if clinically relevant rapid release is claimed and/or onset of action is related to adverse events.
21 An example Propafenone – anti-arrhythmic drug Undergoes extensive first-pass metabolismWide range of half-lifeBioequivalence study undertakenApotex (Generic) v Rhythmol (Reference)300mg tablet18 healthy subjects2-way crossover‘Highly Variable Drugs:Experience with Propafenone’ -Yu Chung Tsang, Radu Pop & Michael Spino
24 Apotex is not Bioequivalent to Rhythmol PK parameters(CV = SD/Mean)Statistical analysisApotex is not Bioequivalent to Rhythmol
25 Reasons for BE failure Very high inter-subject CV for Cmax & AUC High intra-subject variability (46%) from ANOVAPropafenone 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 geneticst1/2 (fast metabolisers) = 2-10ht1/2 (slow metabolisers) = 10-32hDrug levels 5 times higher in slow metabolisers
27 Biosimilars describe officially-approved versions of innovator biological products made by a different sponsor following patent expiry.They are subject to a lengthy approval process which requires substantial additional data compared to chemical generics.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 Regulatory guidanceEMEA 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 EMEA approval for Abseamed 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 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.
30 Non-Clinical studies undertaken PK and PDIn vitro – receptor binding cell proliferationIn-vivo- 5 day PK and PD study in dogToxicologyRepeat dose - 13 weeks in dog2 rabbit studies – various routes of administrationImmunogenicity in dog and rabbit
31 Clinical studies undertaken PK and PD5 PD biomarker studies in healthy volunteers (n=234)All PK parameters evaluatedAbsolute Hb response, reticulocyte countsEfficacy2 double blind randomised group parallel trialsAnaemia due to chronic renal failure (n=478)Chemotherapy induced anaemia (n 114)Safety follow upPatients included = 388Duration = 1 year
32 Useful Regulatory Guidance documents FDA (www.fda.gov/cder/guidance/index.htm)Bioavailability & Bioequivalence studies for orally administered drug products – general considerations – March 2003Statistical approaches to establishing Bioequivalence – January 2001Food-effect Bioavailability & Fed Bioequivalence studies – December 2002Modified 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 1997Dissolution testing of Immediate release solid oral dosage forms - Aug 97Extended release oral dosage forms : Development, Evaluation & Application of In-vitro/In-vivo correlations – Sept 97EMEA (www.emea.europa.eu/index/indexh1.htm)Guideline on the Investigation of Bioequivalence - January Doc. Ref.CPMP/EWP/QWP/1401/98Note for guidance on quality of Modified Release products (A Oral dosage forms; B Transdermal dosage forms) – July 1999Guideline on Similar Biological Medicinal Products – Nov 2004Guideline on Similar Biological Medicinal Products containing Biotechnology-Derived proteins as active substance: Non-Clinical and Clinical issues – June 2005Guideline on Similar Biological Medicinal Products containing Biotechnology-derived Proteins as active substance: Quality Issues – June 2005