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

1

The Role of BioavailabilityThe Role of Bioavailability

in in

Pharmaceutical Product Pharmaceutical Product DevelopmentDevelopment

Alwyn PidgenAlwyn Pidgen November November

20122012

2

Absolute bioavailabilityAbsolute bioavailability

Is the fractionIs the fraction (F)(F) of of unchanged drugunchanged drug absorbed absorbed followingfollowing extravascularextravascular administration when administration when compared to ancompared to an intravenousintravenous dose. dose.

The intravenous dose is assumed to be The intravenous dose is assumed to be completely availablecompletely available

FF can be expressed as either a decimal fraction can be expressed as either a decimal fraction (e.g. 0.8) or as a percentage (e.g. 80%)(e.g. 0.8) or as a percentage (e.g. 80%)

F(abs) = F(abs) = AUC(ev)AUC(ev) * * Dose(iv)Dose(iv) AUC(iv) Dose(ev)AUC(iv) Dose(ev)

3

Relative bioavailabilityRelative bioavailability

Compares the impact of Compares the impact of different dosage forms, different dosage forms, different routes of administrationdifferent routes of administration and and different different dosing conditionsdosing conditions on drug absorption. on drug absorption.

Examples include: - Capsule v Tablet, Oral v Examples include: - Capsule v Tablet, Oral v Rectal, Day time v Night time dosing, Immediate Rectal, Day time v Night time dosing, Immediate release v Modified release.release v Modified release.

F(rel) = F(rel) = AUC(test)AUC(test) * * Dose(ref)Dose(ref) AUC(ref) Dose(test)AUC(ref) Dose(test)

4

Two medicinal products are called Two medicinal products are called Pharmaceutical Pharmaceutical

equivalentsequivalents if they contain the if they contain the same amountsame amount of the of the

same active substancesame active substance in the in the same dosage formsame dosage form, ,

which meet comparable regulatory standardswhich meet comparable regulatory standards ofof

quality, purity quality, purity andand potency. potency.

They may differ in characteristics such as excipients, They may differ in characteristics such as excipients,

shape, scoring and release mechanisms.shape, scoring and release mechanisms.

Pharmaceutical equivalencePharmaceutical equivalence

5

BioequivalenceBioequivalence

Two medicinal products are classed as Two medicinal products are classed as bioequivalent bioequivalent

when their when their raterate and and extentextent of of absorption absorption meet strict meet strict

regulatory requirements after administration of the regulatory requirements after administration of the

same molar dose.same molar dose.

6

Particle size Particle size Solubility (water and lipids)Solubility (water and lipids) Material polymorphism (Crystallisation)Material polymorphism (Crystallisation) Change in Manufacturing processChange in Manufacturing process

HOWEVER -HOWEVER - Pharmaceutical equivalence Pharmaceutical equivalence does not does not

automatically assure automatically assure bioequivalencebioequivalence mainly due mainly due

to changes in to changes in dissolutiondissolution, which can be influenced , which can be influenced

by: -by: -

7

  HOWEVERHOWEVER  Since pharmacologic response is related to circulating Since pharmacologic response is related to circulating drug concentrations – then:-drug concentrations – then:-  Two pharmaceutically equivalent products that give rise Two pharmaceutically equivalent products that give rise to to ‘equivalent’‘equivalent’ concentrations of the concentrations of the active speciesactive species in in blood or plasma (viewed as a profile over time) blood or plasma (viewed as a profile over time) will give will give equivalent therapeutic effectsequivalent therapeutic effects..

KEY CONCEPT IN BIOEQUIVALENCEKEY CONCEPT IN BIOEQUIVALENCE ‘‘Equal amounts of the same drug administered in Equal amounts of the same drug administered in equivalent products will show equal therapeutic equivalent products will show equal therapeutic effects’.effects’.A A directdirect demonstration of demonstration of therapeutic equivalencetherapeutic equivalence requires an expensive clinical (efficacy/safety) trialrequires an expensive clinical (efficacy/safety) trial

8

Why perform Bioequivalence studies Why perform Bioequivalence studies ??

To enable clinical trial formulations to be To enable clinical trial formulations to be modified or production ‘scaled up’ modified or production ‘scaled up’ throughout a drug’s development (NDA).throughout a drug’s development (NDA).

To compare a clinical trial formulation with the To compare a clinical trial formulation with the ‘to be marketed’ product just prior to filing ‘to be marketed’ product just prior to filing (NDA).(NDA).

To compare a generic drug product with a To compare a generic drug product with a corresponding reference drug (ANDA). corresponding reference drug (ANDA).

For post- approval formulation changes For post- approval formulation changes undertaken by the ‘innovator’ company (NDA).undertaken by the ‘innovator’ company (NDA).

9

When are bioequivalence studies not normally When are bioequivalence studies not normally

needed ?needed ?

If the product differs only in the If the product differs only in the strength of the strength of the active substanceactive substance it contains and the it contains and the pharmacokinetics are linearpharmacokinetics are linear

If the product has been If the product has been slightly reformulatedslightly reformulated or or the manufacturing method slightly modified by the manufacturing method slightly modified by the original manufacturer in ways that can be the original manufacturer in ways that can be argued to be irrelevant argued to be irrelevant (using approved in-vitro (using approved in-vitro tests)tests)

If the product is to be administered If the product is to be administered parenterallyparenterally as a solution and contains the same active as a solution and contains the same active substances and excipients as a medicinal productsubstances and excipients as a medicinal product currently approvedcurrently approved..

10

If the product is a If the product is a liquid oral form in solutionliquid oral form in solution containing the active substance in the same containing the active substance in the same concentration and form as a concentration and form as a currently approved currently approved medicinal productmedicinal product

An An acceptable correlationacceptable correlation between dissolution between dissolution rate in-vivo and in-vitro has been shown (FDA rate in-vivo and in-vitro has been shown (FDA regulation).regulation).

Products intended for Products intended for local uselocal use to act to act without without systemic absorptionsystemic absorption

11

Healthy volunteersHealthy volunteers

Male subjects or women of non-child bearing Male subjects or women of non-child bearing potentialpotential

Aged between 18 and 55Aged between 18 and 55

Weight within accepted normal BMI valuesWeight within accepted normal BMI values

Single dose.Single dose.

2-period Crossover design2-period Crossover design

Typical Study Design FeaturesTypical Study Design Features

12

PeriodPeriod

11 22

Subjects within Sequence Subjects within Sequence 11

RR TT

Subjects within Sequence Subjects within Sequence 22

TT RR

Crossover DesignCrossover Design

R = Reference and T = Test formulationR = Reference and T = Test formulation

Ensures a Ensures a within subjectwithin subject comparison – most comparison – most efficient design.efficient design.

A A washout interval washout interval between periods ensures that between periods ensures that all the active ingredient from the first treatment all the active ingredient from the first treatment has been has been cleared from the bodycleared from the body before before administration of the second treatment.administration of the second treatment.

13

Should be appropriately Should be appropriately statistically poweredstatistically powered if study is pivotal for filingif study is pivotal for filing

An estimate of a drug’s An estimate of a drug’s intrinsic (within intrinsic (within subject) variabilitysubject) variability is obtained from previous is obtained from previous studies or publicationsstudies or publications

Should not be smallerShould not be smaller than 12 than 12

SAMPLE SIZESAMPLE SIZE

14

The main The main active metaboliteactive metabolite of an inactive of an inactive pro-pro-drug drug should be measured if the plasma levels of should be measured if the plasma levels of the the parentparent are are too lowtoo low for accurate assay for accurate assay measurement.measurement.

WHAT TO MEASUREWHAT TO MEASURE

Plasma concentrations of the Plasma concentrations of the parent drugparent drug are are generally recommended.generally recommended.

Parent drug is more sensitive to formulation changes Parent drug is more sensitive to formulation changes than any (subsequently formed) metabolite.than any (subsequently formed) metabolite.

15

Enantiomers versus RacematesEnantiomers versus Racemates

Measurement of the Measurement of the racemate racemate is recommendedis recommended..

Measurement of Measurement of individual enantiomersindividual enantiomers is only is only recommended if they have different PK or PD recommended if they have different PK or PD characteristicscharacteristics

Fixed combinationsFixed combinations

Separate analyses are performed for Separate analyses are performed for each active each active substancesubstance when assessing the Bioequivalence of when assessing the Bioequivalence of the the fixed combination fixed combination product versus co- product versus co- administration of the administration of the individual individual products. products.

16

Peak exposure (CPeak exposure (Cmaxmax))

Important parameter - may be linked to safety and/or Important parameter - may be linked to safety and/or efficacy.efficacy.

PHARMACOKINETIC PARAMETERSPHARMACOKINETIC PARAMETERS

Early exposureEarly exposure

Only consider if previous clinical studies indicateOnly consider if previous clinical studies indicate that rapid release is linked to adverse events.that rapid release is linked to adverse events.

Parameters may includeParameters may include AUC( AUC(0–tmax0–tmax))andand t tmaxmax

tmaxtmax

17

ParametersParameters

AUC to the last measurable time point AUC to the last measurable time point (AUC(AUC0-t0-t)) AUC extrapolated to infinite time AUC extrapolated to infinite time (AUC(AUC0-inf0-inf)) AUC truncated at 72h AUC truncated at 72h (AUC(AUC0-720-72)) – (long half-life drugs – (long half-life drugs

only)only)

Other considerationsOther considerations

o The elimination rate constant The elimination rate constant (k(kelel)) and terminal half- and terminal half-life life (t(t1/21/2)) should be reported - particularly if should be reported - particularly if AUC(AUC(0-inf0-inf)) is used.is used.

Total exposure (AUC)Total exposure (AUC)

Generally, the most important BE parameter since AUC Generally, the most important BE parameter since AUC is is directlydirectly proportional to the amount of drug proportional to the amount of drug absorbed.absorbed.

18

STATISTICAL ANALYSISSTATISTICAL ANALYSIS

Calculate 90% Calculate 90% confidence intervals (CI)confidence intervals (CI) of the ratio of the ratio of the treatment means (test/reference) for of the treatment means (test/reference) for CmaxCmax, , and and AUCAUC..Log transformed data prior to analysisLog transformed data prior to analysis..

If statistical evaluation of If statistical evaluation of tmaxtmax is required then a is required then a non-parametric significance testnon-parametric significance test is performed on the is performed on the untransformed data.untransformed data.

19

90%90%confidenceconfidence

5% 5% riskrisk

5% 5% riskrisk

lower limitlower limit0.80.8

90% confidence interval for BE90% confidence interval for BE

upper limitupper limit1.251.25

TT

RR

0.8 0.8 ≤≤

testtest

refref

≤ ≤ 1.251.25

20

tmaxtmax : Only consider : Only consider if clinically relevant rapid release is if clinically relevant rapid release is claimed and/or onset of action is related to adverse events.claimed and/or onset of action is related to adverse events.

AUCAUC : 90% CI for test treatment to be within : 90% CI for test treatment to be within ≥≥ 0.8 and 0.8 and ≤≤ 1.25 of the reference treatment (FDA and EMEA)1.25 of the reference treatment (FDA and EMEA)

Range to be tightened in the case of a drug with a narrow Range to be tightened in the case of a drug with a narrow therapeutic window (e.g. digoxin, phenytoin) (FDA and therapeutic window (e.g. digoxin, phenytoin) (FDA and EMEA). This may also be applicable to Cmax.EMEA). This may also be applicable to Cmax.

CmaxCmax : 90% CI for : 90% CI for test treatment to be within test treatment to be within ≥≥ 0.8 and 0.8 and ≤≤ 1.25 1.25 of the reference treatmentof the reference treatment (FDA and EMEA)(FDA and EMEA)

A wider interval may be clinically acceptable (see guidelines). A wider interval may be clinically acceptable (see guidelines). Within-subject variability (%CV) for CmaxWithin-subject variability (%CV) for Cmax is generally higheris generally higher than AUC. Cmax is also highly dependent upon sampling times.than AUC. Cmax is also highly dependent upon sampling times.

The Regulatory acceptance criteriaThe Regulatory acceptance criteria

21

Propafenone – anti-arrhythmic drugPropafenone – anti-arrhythmic drug Undergoes extensive first-pass metabolismUndergoes extensive first-pass metabolism Wide range of half-lifeWide range of half-life

Bioequivalence study undertakenBioequivalence study undertaken

Apotex (Generic) v Rhythmol (Reference)Apotex (Generic) v Rhythmol (Reference)

300mg tablet 300mg tablet

18 healthy subjects18 healthy subjects

2-way crossover2-way crossover

An exampleAn example

‘‘Highly Variable Drugs:Experience with Propafenone’ -Highly Variable Drugs:Experience with Propafenone’ -Yu Yu Chung Tsang, Radu Pop & Michael SpinoChung Tsang, Radu Pop & Michael Spino http://www.ualberta.ca/~csps/JPPS1(2)/Y.Tsang/Tsang.pdfhttp://www.ualberta.ca/~csps/JPPS1(2)/Y.Tsang/Tsang.pdf

22

Mean Plasma concentrationsMean Plasma concentrations

23

Individual variabilityIndividual variability

24

PK PK parameterparameter

ss

Statistical Statistical analysisanalysis

(CV = (CV = SD/Mean)SD/Mean)

Apotex is not Bioequivalent to Apotex is not Bioequivalent to RhythmolRhythmol

25

Reasons for BE failureReasons for BE failure

Very high Very high inter-subjectinter-subject CV for Cmax & AUC CV for Cmax & AUC

High High intra-subjectintra-subject variability (46%) from variability (46%) from ANOVAANOVA

Propafenone falls into the category of a ‘highly Propafenone falls into the category of a ‘highly variable drug’ – hence sample size used was variable drug’ – hence sample size used was inadequate.inadequate.

Variability in elimination characteristics due to Variability in elimination characteristics due to the the metabolismmetabolism of propafenone being of propafenone being influenced by influenced by geneticsgeneticso tt1/21/2 (fast metabolisers) = 2-10h (fast metabolisers) = 2-10ho tt1/21/2 (slow metabolisers) = 10-32h (slow metabolisers) = 10-32ho Drug levels 5 times higher in slow metabolisersDrug levels 5 times higher in slow metabolisers

26

BIOLOGICAL PRODUCTSBIOLOGICAL PRODUCTS

27

They are subject to a lengthy approval process which They are subject to a lengthy approval process which requires requires substantial additional datasubstantial additional data compared to compared to chemical generics.chemical generics.

Biosimilars Biosimilars describe officially-approved versions of describe officially-approved versions of innovator biological products made by a different innovator biological products made by a different sponsor following patent expiry.sponsor following patent expiry.

Biological products are generally derived from Biological products are generally derived from living living materialmaterial - human, animal, or micro-organism - are - human, animal, or micro-organism - are complex in structure and can be difficult to replicate. complex in structure and can be difficult to replicate. 

Unlike the more common small-molecule drugs, Unlike the more common small-molecule drugs, biologics can be biologics can be sensitive to changes in sensitive to changes in manufacturing processesmanufacturing processes and copies may and copies may perform perform differentlydifferently than the original than the original branded productbranded product

28

Regulatory guidanceRegulatory guidance

EMEAEMEA guidance available since 2005 - several guidance available since 2005 - several ‘similar medical products’ approved under this ‘similar medical products’ approved under this process.process. Growth hormone (Omnitrope – Sandoz)Growth hormone (Omnitrope – Sandoz) Erythropoietin (Abseamed – Medice Arzneimittel Putter)Erythropoietin (Abseamed – Medice Arzneimittel Putter) Granulocyte-Colony Stimulating Factor (Tevagrastim – Granulocyte-Colony Stimulating Factor (Tevagrastim –

Teva Generics)Teva Generics)

FDAFDA used a similar approval process to the EMEA used a similar approval process to the EMEA for Biosimilars - but decided new legislation was for Biosimilars - but decided new legislation was needed. This was passed in 2010 – still awaiting needed. This was passed in 2010 – still awaiting new approvals under this process.new approvals under this process.

29

Abseamed is an injectable solution (i.v. or s.c.) to Abseamed is an injectable solution (i.v. or s.c.) to treat treat anaemiaanaemia in patients with in patients with chronic renal failurechronic renal failure or or patients on patients on chemotherapychemotherapy..

The The reference product reference product EprexEprex containscontains epoetin alfaepoetin alfa which is a man-made version of which is a man-made version of ErythropoietinErythropoietin (EPO). (EPO).

EPO is produced EPO is produced naturallynaturally in the body mostly by the in the body mostly by the kidneyskidneys. It stimulates the bone marrow to produce . It stimulates the bone marrow to produce red red blood cellsblood cells. .

When the body does not produce enough EPO - When the body does not produce enough EPO - severe anaemia can occur.severe anaemia can occur. Epoetin alfa is then Epoetin alfa is then administered to provide the necessary stimulus to the administered to provide the necessary stimulus to the bone marrow.bone marrow.

EMEA approval for AbseamedEMEA approval for Abseamed

30

Non-Clinical studiesNon-Clinical studies undertaken undertaken

PK and PDPK and PD

In vitro – receptor binding cell proliferationIn vitro – receptor binding cell proliferation

In-vivo- 5 day PK and PD study in dogIn-vivo- 5 day PK and PD study in dog

ToxicologyToxicology

Repeat dose - 13 weeks in dogRepeat dose - 13 weeks in dog

2 rabbit studies – various routes of administration 2 rabbit studies – various routes of administration

Immunogenicity in dog and rabbitImmunogenicity in dog and rabbit

31

Clinical studies undertakenClinical studies undertaken

PK and PDPK and PD

5 PD biomarker studies in healthy volunteers (n=234)5 PD biomarker studies in healthy volunteers (n=234)

All PK parameters evaluatedAll PK parameters evaluated

Absolute Hb response, reticulocyte countsAbsolute Hb response, reticulocyte counts

EfficacyEfficacy

2 double blind randomised group parallel trials2 double blind randomised group parallel trials Anaemia due to chronic renal failure (n=478)Anaemia due to chronic renal failure (n=478) Chemotherapy induced anaemia (n 114)Chemotherapy induced anaemia (n 114)

Safety follow upSafety follow up

Patients included = 388Patients included = 388

Duration = 1 yearDuration = 1 year

32

FDA FDA (www.fda.gov/cder/guidance/index.htm)(www.fda.gov/cder/guidance/index.htm) Bioavailability & Bioequivalence studies for orally administered drug Bioavailability & Bioequivalence studies for orally administered drug

products – general considerations – March 2003products – general considerations – March 2003 Statistical approaches to establishing Bioequivalence – January 2001Statistical approaches to establishing Bioequivalence – January 2001 Food-effect Bioavailability & Fed Bioequivalence studies – December Food-effect Bioavailability & Fed Bioequivalence studies – December

2002 2002 Modified Release Solid Oral Dosage Forms - Scale-Up and Post-approval Modified Release Solid Oral Dosage Forms - Scale-Up and Post-approval

Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation – Sept 1997Testing and In Vivo Bioequivalence Documentation – Sept 1997

Dissolution testing of Immediate release solid oral dosage forms - Aug Dissolution testing of Immediate release solid oral dosage forms - Aug 9797

Extended release oral dosage forms : Development, Evaluation & Extended release oral dosage forms : Development, Evaluation & Application of In-vitro/In-vivo correlations – Sept 97Application of In-vitro/In-vivo correlations – Sept 97

EMEA (www.emea.europa.eu/index/indexh1.htm)EMEA (www.emea.europa.eu/index/indexh1.htm) Guideline on the Investigation of Bioequivalence - January 2010 - Doc. Guideline on the Investigation of Bioequivalence - January 2010 - Doc.

Ref.CPMP/EWP/QWP/1401/98Ref.CPMP/EWP/QWP/1401/98 Note for guidance on quality of Modified Release products (A Oral Note for guidance on quality of Modified Release products (A Oral

dosage forms; B Transdermal dosage forms) – July 1999dosage forms; B Transdermal dosage forms) – July 1999 Guideline Guideline on Similar Biological Medicinal Productson Similar Biological Medicinal Products – Nov 2004– Nov 2004 Guideline on Similar Biological Medicinal Products containing Guideline on Similar Biological Medicinal Products containing

Biotechnology-Derived proteins as active substance: Non-Clinical and Biotechnology-Derived proteins as active substance: Non-Clinical and Clinical issues – June 2005Clinical issues – June 2005

Guideline on Similar Biological Medicinal Products containing Guideline on Similar Biological Medicinal Products containing Biotechnology-derived Proteins as active substance: Quality Issues – Biotechnology-derived Proteins as active substance: Quality Issues – June 2005June 2005

Useful Regulatory Guidance documentsUseful Regulatory Guidance documents