NON CLINICAL DEVELOPMENT OF NON CLINICAL DEVELOPMENT OF DRUG SPECIALITIESDRUG SPECIALITIES

________________________________________________

Bernard MARCHANDBernard MARCHAND

ExploExploExploExplo

ProjecProjectt

ProjecProjectt

Preclinical Preclinical Stage AStage A

Preclinical Preclinical Stage AStage A Phase IPhase IPhase IPhase I Phase Phase

IIIIPhase Phase

IIII

Phase IIIPhase IIIPhase IIIPhase III NDANDANDANDA

Post Post NDANDAPost Post NDANDA

Preclinical Preclinical Stage BStage B

Preclinical Preclinical Stage BStage B

BioPharmaceutica

l Research

TOXICOADME

Salt Selection

Phase IFormulatio

n

PK Interaction

s

PB/PK

PK/PD

Up scaled Formulatio

n

Toxicological and kinetics Expertises

PopulationKinetic

Interspecies

metabolismcomparison

Pharmaceutical File

NewFormulation

Pharmaceutical

Support Regulatory

Affairs

Pharmacopoeia

Copy Analysis

PharmacokineticPharmacokineticToxicologyToxicology

PhysicochemistryPhysicochemistryPreclinical Preclinical DevelopmentDevelopment

New targets New tools comingfrom development

RESEARCHPHARMACOLOGY

CHEMISTRY

StructureActivity

Relationships

BIOPHARMACEUTICALSCREENING

DEPARTMENT

Hits Identification

Lead Optimisation

Candidat Selection

Analytical methods, Absorption

Metabolic stabilitySolubility,Specific

questions...

HTS SDSPreclinical

DevelopmentClinical

Trial

1 drug1- 3 drugs30 - 3 drugs300 - 30 drugs

Lead Optimisation Back-up

Intestinal absorption P450 Isoenzymes Metabolic Stability Inhibition Metabolic pathway Induction Other parameters BBB permeation/Cell toxicity

DISCOVERY PROCESS & BIOPHARMACY DESCRIPTORS

MAJOR TECHNICAL EVOLUTIONS IN BIOPHARMACY

* ** ** * * * * * * * * * * * * * * * **HPLC

LC/MS/MS

ANALYTICAL

DETECTION

SAMPLE PREPARATION

CELLLULAR MODELS(Caco2, hepatocytes)

GENETIC TOOLS(Human DNA)

Automation (96 wells)

SUBCELLULARMODELS

Hepatic Microsomes(animal +

man)

BIO INFORMATIC

Data Analysis Modelisation

Cassette Dosing

ABSORBED FRACTION

SOLUBILITY

Fraction of the dosesolubilised

in the intestin

SOLUBILITY

Fraction of the dosesolubilised

in the intestin

ABSORBEDFRACTION

PERMEABILITY SOLUBILITY

LIPOPHILY

PERMEABILITY

Molecular WeightNitrogenOxygene

Hydrogen BondsIonisation

PERMEABILITY

Molecular WeightNitrogenOxygene

Hydrogen BondsIonisation

Caco2 PERMEABILITY MODEL

Different Transport Mechanisms

- Transcellular (passive)(lipophilic)

- Paracellular (passive)(hydrophilic)

- Transcellular (active) (transportors)- Efflux Process

(PGP)

HUMAN ENTEROCYTE CELLS

Intestin

Liver

GeneralCirculation

HEPATIC BARRIER

Metabolism Rate

Component of theterminal half time

Metabolic Bioavailability (first pass effect)Metabolism

rapidity

LIPOPHILY

PREDICTION OF IN VIVO METABOLIC BIOAVAILABILITY

Km vitro

Vm vitro

Km vivo

Vm vivo

g prot/g liver and g liver/animal

MetabolicBiovailability

Q*fu*Vm*S/(Km+S)BloodFlow

Q+fu*Vm*S/(Km+S)

PlasmaProteins

Concentration IN

ConcentrationOUT

MetabolitesConcentration

Ka Dose

SIMULATION IN RELATION TO DOSE

predicted clinical doses

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0,01

0,08

0,64

5,12

40,9

6

327,

68

2621

,44

SimLin

Dose (mg/kg)

DOG

++

+

MAN

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0,01

0,08

0,64

5,12

40,9

6

327,

68

2621

,44

SimLin

Dose (mg/kg)

+

RATRAT

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0,01

0,08

0,64

5,12

40,9

6

327,

68

2621

,44

2097

1,52

SimLin

Dose (mg/kg)

+ ++

Met

abo

lic

Bio

ava

ilab

ilit

y

Bio

dis

po

nib

ilit

é m

étab

oli

qu

e

Bio

dis

po

nib

ilit

é m

étab

oli

qu

e

In vivo/In vitrocorrelation in one species :Mixture of products (cassette dosing 5/Rat - 50/Dog

1A2

6%2A62%

2C910%

2C194%

2D630%

2E1

5%

3A443%

NATURE AND NUMBER OF INVOLVED P450

Interest in screening :- Avoid one polymorphic enzyme- Avoid metabolism by only one P450

MetabolicStability

± specific inhibitors

Enterocyte humain : transport et métabolisme

UGTUGT 1A61A6 3A43A4 UGTUGT 2B22B277 3A43A4

hOATP-B(?)

MRP-3

MRP-1

MRP-(5?)

BCRP

ISBT

LRP

MRP-1(?)

MRP-2

P-gp (MDR-1)

PepT1

ASBT

Na+/SLGT1

SPNT1Dipeptide

TripeptideTransporters

MCT(drug/H+co-transporter)

SANG

VEINE

PORTE

I

N

T

E

S

T

I

N

Noyau 1A1A11

3A3A44

1A1A22

Jonctions Jonctions serréesserrées

Jonctions serréesJonctions serrées

BLOOD BRAIN BARRIER MODELE

Transport Study(filter +/- cells)

Astrocytes(confluent in 3

weeks)Ringer HEPES

Drug

6 wales plates

BBCE (confluent and differenciatedin 1 week and

ready to use for 5 days)

Basolateral

ApicalLC-MS-MS

Quantitation

(10, 15, 20, 30, 45 min)

Co-culture of Bovin Brain Capillary Endothelial Cellswith rat astrocytes (Pr Ceccheli - Lille)

CORRELATION Caco2/BHE

-13

-12

-11

-10

-9

-8

-7

-6

-10 -9 -8 -7 -6 -5 -4

Log Papp BBB

Lo

g P

ap

p C

ac

o2

Mannitol

TerbutalinePipenzepine

SucroseUrée

Dopamine

Ac Acetylsalicylique

NicotineDexamethazonePindolol

HydrocortisonePropanolol

CafeinePhenytoin

DiazepamR = 0.74

SCREENING IN TOXICOLOGY

MutagenesiMutagenesiss

MutagenesiMutagenesissAmes II

Automatised Micronucleus ?

Morphology, Viability, Glutathion level

Cellular Toxicology with cryopreserved Cellular Toxicology with cryopreserved hepatocytes ? hepatocytes ?

Cellular Toxicology with cryopreserved Cellular Toxicology with cryopreserved hepatocytes ? hepatocytes ?

In vitro model answering in vivo issues In vitro model answering in vivo issues In vitro model answering in vivo issues In vitro model answering in vivo issues Ex : vacuolisation on cultured fibroblastes

Toxicogenomics ?Toxicogenomics ? Toxicogenomics ?Toxicogenomics ?

Global approach

Significant geneinduction or repression

Cells / Tissues RNA Hybridization

Database mining and mecanistic interpretation

Image analysis

TOXICOGENOMICS

maxmin

Control Phenobarbital

CYP2BCYP3A

RESULTS

Gene Category Selected Genes

•Apoptosis

•Cell cycle

•DNA damage/Repair

•Inflammation

•Oncogene

•Stress response

•Peroxisome Proliferators

•Transcription factors, growth factors

•Plasma transport

•Phase I

•Phase II

•Phase 0/III

•CYPs regulating nuclear factors

•Bax, Bcl-2, Bcl-X, c-myc, c-fos, caspase 7-8,CD 27, TNF, Smp30

•Cyclin A-B1- D1/2/3-E1, cdK 2-4-6,JNK-1, Telomerase

•GADD45, GADD153, MGMT, p16, poly(ADP-ribose) synthetase

•IL 1, IL-6 ,IL11, IL-15, cyclooxygenase-2

•c-jun, c-myc, elk-1

•Oxidative stress genes, ApoJ, Hsp70, Heme oxygenase 2, SOD

•Enoyl coA hydratase, PPAR , Acyl coA oxidase

•C/EBP, IB-, NFB, erk-1, p38, HGF, TGFB RII

•albumin, transferrin

•CYP P450s (22), FMO, EH, MAO

•GST (4), UGT(10), SULT(4)

•MDR1, MRP (6), BSEP, OATP (4), OAT (2), OCT (2)

•CAR, PXR, RXR, GR

175 human genes involved in drug metabolism at the hepatic level

HANDLING THE DATA

Databases for correct data use, the new challenge for tomorrow ?

Tools for rapid assessment of metabolism are available but how we handle the data has not yet been completely mastered

Data base

Log K ’CalculatedLogP, Rate of metabolism

Solubility, LogP Caco-2 Papp Microsomal Km/Vm IC50 inhibition n-in-one dosing CYP450 Km, Vm Ki

inhibition constant induction potential

n-in-one dosing

in Man ?Sorting molecules with Warnings and Metabolic SAR

Sorting molecules with in vivo scaled up data and Metabolic QSAR

Sorting molecules with partial or

total rebuilding of the entire population

Theoretical approach

HTS SDS

Preclinicaldevelopmen

t

1st administration to Man

Back up

PRECLINICAL STUDYPRECLINICAL STUDY PROGRAMMEPROGRAMME

Stage BStage A4 months4 months 6 6 monthsmonths

-Dose Ranging (3-7d) Rat + Non-Rodt- Ames test- Mouse Lymph.

-Drug Subst. Analyt. Chem.- Degradation

- 4 wk Tox Rat + Non-Rodt- Acute studies Rat + Mouse PO & IP or IV- Rat Bone Marrow micronucleus

- Choice of Salt- Tablet Formul. + Stability

- Assay Validation- Plasma Stability- TK 4 wk Rat- TK 4 wk Non-Rodt- TK Micronucleus- Def. PK Non-Rodt- Induct. Potential Rat + Non-Rdt* * if Rat positive - Enzymes identif. (human)- Intersp. Comp. 14C- Label. Cpd

- Assay developt- TK DoseRanging Rat+ Non-Rodt- PK Rat - Prel. PK Non-Rodt- Blood/Pl.Ratio- Prel. Metab. in vivo Rat- Prel. Prot. Bind. - Inhib. Potential- Intersp. Comp.- Feasibility label. cpd

200 g200 g 2.5 kg2.5 kg

Regulatory Toxicology – Early Programme #

Phase I requirements *Single dose toxicityRepeat dose toxicity studiesGenotoxicity studiesReproductive toxicity studies

* Other requirements

Pharmacology (actions relevant to the proposed route)Safety pharmacologyPharmacokinetics (preliminary studies on absorption, distribution, metabolism and excretion) and in vitro metabolism studies

## ICH M3 : Nonclinical Safety Studies ICH M3 : Nonclinical Safety Studies

Regulatory Toxicology – Later Programme #

Phase II, III marketing application requirements *Chronic dose toxicity studiesCarcinogenicity studiesReproductive toxicity studiesAppropriate toxicity/genotoxicity studies on metabolites,impurities and/or excipient

* Other requirements

Additional safety pharmacology (if necessary)Additional genotoxicity studies (if necessary)Phamacokinetics (studies on absorption, distribution, metabolism and excretion)

## ICH M3 : Nonclinical Safety Studies ICH M3 : Nonclinical Safety Studies

Duration of Toxicity Studies #

* NOTE in US and EU, as an alternative to repeat dose studies, single dose toxicity studies with extended examinations may support single dose human trials

Minimum duration of toxicity

Duration of clinical trials Rodent Non –rodent

Single dose 2 weeks* 2 weeks

Up to 2 weeks 2-4 weeks* 2 weeks

Up to one month one month one month

Up to 3 months 3 months 3 months

Up to 6 months 6 months 6 months - 1year

> 6 months 6 months 1 year

To support phase I and II trials in EU and phase I, II and III trials

## ICH M3 : Nonclinical Safety Studies ICH M3 : Nonclinical Safety Studies

The battery can be completed with additional test(s) when necessary.Should permit to discard at the beginning of development potential genotoxic carcinogen compounds

AMES TEST: detection of reverse mutation on

S. typhimurium and E. coli (= procaryotes)

MOUSE LYMPHOMA : detection of forward mutation on cell lineage (= eucaryotes)can also detect clastogenic effects

IN V

ITRO

IN V

ITRO

IN

VIV

O

IN V

IVO

MICRONUCLEUS on rat bone marrow: detection of chromosome breaks = clastogenicity

PRECLINICAL STUDIES

GENOTOXICITY : Standard Test Battery

- ACUTE :Route: intended for human -If oral route for human : ORAL + PARENTERAL (IV or IP)

Species: MOUSE and RAT

Examinations : MORTALITY CLINICAL SIGNS/ BEHAVIOR

GROSS OBSERVATION AT NECROPSY (Histopathology for gross lesions)

Acute toxicology profileMNLD = Maximal non-lethal

dose MLD = Minimal lethal dose

PRECLINICAL STUDIES

GENERAL TOXICOLOGY

- SUBCHRONIC and CHRONIC

Route : intended for human

Species : Rodent = RATNon-Rodent = DOG or MONKEY

Dosing : daily (or twice daily), 3 doses + control

Duration : up to 6 months (rodents)

9 to 12 months (non-rodents)

Investigations : pluridisciplinary contributions

Define NOEL : No Effect Level or

NOAEL: No Adverse Effect Level

TARGET ORGANS - BIOMARKERS

PRECLINICAL STUDIES

GENERAL TOXICOLOGY

Clinical observationsbehavior

Toxicokinetic/Metabolism (enzyme induction/inhibition)

BodyweightFood/Water intakes

Necropsy Gross observations

40 organs/tissue samplesHistology process

Histopathology Electronmicroscopy

Urinalysis

BloodHematologyred, white cells andplatelet countsBiochemistry20 to 25 parameters

STANDARD TOXICOLOGY EVALUATIONS

- EMBRYOFETAL TOXICOLOGY :

Hysterectomy- uterus content: implantations,

resorptions…- external- visceral examinations of fetus- skeletal

Teratogenic effect?

- FERTILITY : Reproductive performance

Male : sperm analysis+ histopathology of

gonads and accessory glands

Female : oestrus cycle

PRECLINICAL STUDIES

REPRODUCTIVE TOXICOLOGY

- PERI-and POSTNATAL TOXICOLOGY

Parturition

Lactation

Physical, sensory and behavioral development of pups

Second generation study

Species : Rodent = RAT + Non Rodent = RABBIT (Lagomorph)

for embryofetal studies

PRECLINICAL STUDIES

REPRODUCTIVE TOXICOLOGY (contld)

These studies remain necessary to detect non-genotoxic carcinogens.

Two species: RAT and MOUSETwo-year duration: LIFE SPAN for these species

Investigations :

. Clinical observations and mortality

. Feed and water intakes

. Palpations: for detection of masses (subcutaneous, mammary

glands,…). Necropsygross observationsorgan weightshistomorphologic evaluations 40 tissues or organs + masses

. Statistical analysis Conclusion about carcinogenic potential

PRECLINICAL STUDIES

CARCINOGENESIS

PlasmaConcentration

1000

100

10

0 1 2 3 45

Time (h)

Toxicity treshold

Peak effect

Toxic effectsToxicokinetic

s

Pharmacologic effects

Pharmacokinetics

TOXICOLOGY

Toxicological Requirement

Depending on toxicity, a frequently used “safety margin” for volunteer studies is 10 fold between dose which produces toxicity in animals and dose given to humans

First dose can be 1/100 of NOAEL

Final dose can be 1/10 of NOAEL

Plasma data on drug will give levels at which toxic effects may be expected and so must not be exceeded

Awareness that animal data not necessarily predict clinical toxicity

PRECLINICAL STUDYPRECLINICAL STUDY PROGRAMMEPROGRAMME

Pre- ProjectPre- Project

Stage BStage A

4 months4 months 6 months6 months 2 months2 months1 month1 month

Decision PointPreclinical Research

- Dose Ranging (3-7d) Rat + Non-Rodt- Ames test- Mouse Lymph.

- Drug Subst. Analyt. Chem.- Degradation

- 4 wk Tox Rat + Non-Rodt- Acute studies Rat + Mouse PO & IP or IV- Rat Bone Marrow micronucleus

- Choice of Salt- Tablet Formul. + Stability

- Assay Validation- Plasma Stability- TK 4 wk Rat- TK 4 wk Non-Rodt- TK Micronucleus- Def. PK Non-Rodt- Induct. Potential Rat + Non-Rdt* * if Rat positive - Enzymes identif. (human)- Intersp. Comp. 14C- Label. Cpd

Check List

Preclinical SummaryBoard Committee

Development Decision

- Production clinical batch Phase I (capsule)

Investigator brochure

- Clinical Assay- Plasma Stab. (man)- TK assay (transfer to CRO)- TK Dose Ranging ReproTox - WBA Rat- Mass Bal. Rat & in vivo Met. - Def. Prot. Bind. (label. cpd)

- Dose Ranging ReproTox

- Assay developt- TK DoseRanging Rat+ Non-Rodt- PK Rat - Prel. PK Non-Rodt- Blood/Pl.Ratio- Prel. Metab. in vivo Rat- Prel. Prot. Bind. - Inhib. Potential- Intersp. Comp.- Feasibility label. cpd

16 kg16 kg200 g200 g 2.5 kg2.5 kg

IMPD

PHASE 1 STUDIES

Clinical PharmacokineticsClinical PharmacokineticsPhase I : dose Phase I : dose tolerancetolerance

0 6 12 18 24

Time (h)

1

10

100

1000

10000

Co

ncen

trati

on

0

5

10

15

20

0 30 60 90 120

Dose

AU

C

Dosing 600-900 samples in real time

TARGETORGANS

(TISSUES)

TARGETORGANS

(TISSUES)

GASTRO INTESTINAL TRACT

BLOOD CIRCULATION

First pass effect

Portal vein

LIVER

1

10

100

1000

0 4 8 12 16 20 24Time (h)

Co

nce

ntr

atio

n

ABSORPTION

DISTRIBUTION

Cmax

tmax

+ ELIMINATION

Administration

EXCRETION

Bile

AUC Exposure

ORAL ROUTEORAL ROUTE

SINGLE DOSE PK

1

10

100

1000

0 4 8 12 16 20 24

Time (h)

Con

cen

trat

ion

1

10

100

1000

0 4 8 12 16 20 24

Time (h)

Con

cen

trat

ion

Integration of physiological parameters and in vitro measurements

Qtissues

Qmuscles

Q portal v.

Q hepatic. a

Qheart

Kp liver

Vmax Km fabs

Kpheart

Kplung

Kptissues

Kpmuscles

BioavailabilityInter/intra

subjectvariabilit

y

Drug-drug interaction

Intestinal absorption

Metabolic stability

Metabolic pathways

P450 Isoenzymes

Inhibition potential

Induction potentialPrediction of the main drug characteristics with respect to the entire population

Rebuild (predict) of the in vivo situation

Evaluation of simple drug metabolism

parameters

DMPK ISSUES IN DRUG DEVELOPMENT

PREDICTIONS IN VIVO

Interindividual variability

CYP1A1 CYP1A2CYP1A1 CYP1A2

CYP2C9CYP2C9

Extreme subjects of

the simulation

Time (h)Time (h)

Con

cen

trat

ion

(µ

M)

Con

cen

trat

ion

(µ

M)

IN VIVO PREDICTIONSIN VIVO PREDICTIONS

Drug-drug interactionsDrug-drug interactions

1

10

100

1000

Con

cen

trat

ion

0 4 8 12 16 20 24

Time (h)

+ inductor

+ inhibitor

+

+

PHASE II PK/PD

0

50

100

150

200

0 50 100 150 200 250 300 350 400 450

concentration

Eff

ect

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

0

10

20

30

40

50

60

70

80

Effect

Cp

Ce

Direct Direct effecteffectEffectEffect versus Cpversus Cp

Delayed effectDelayed effectEffect versus Ce

PharmacokineticPharmacokinetic / / Pharmacodynamic AnalysisPharmacodynamic Analysis

0

100

200

300

400

500

600

700

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

0

20

40

60

80

100

120

140

Effect

Plasmaconcentration

Cp

Simulations

Dissolution model :Relationship between In vitro and In vivo dissolution

PK/PD model :Relationship between plasma concentrations and effects

Pharmacodynamicobjectives

Sustained releaseformulation

Why a modelling approach?

A clinical studyper formulation

PK model : Absorption, distribution, elimination

FORMULATION RESEARCH

Oral RouteOral RouteTablets and CapsulesFast Dissolving Forms

Slow Release FormulationDelayed Formulation

Injectable RouteInjectable RouteBolus and Infusion

Slow Release Formulation

Transdermal RouteTransdermal RoutePatches

Iontophoresis devices

Transmucosal RouteTransmucosal RouteBuccalNasal

Pulmonary

ORAL ROUTE/PROLONGED RELEASEHYDROPHILIC MATRIX

Gastro intestinal fluids penetrate the polymer layer which, consequently, swells and forms a gel which controls the release kinetics of the drug substance

H2O

HPMC

ORAL ROUTE / HYDROPHILIC MATRIX

In vitro dissolution profile

0

50

100

0 4 8 12 16

Prolonged Release

Immediate Release

%

H

ORAL ROUTE / HYDROPHILIC MATRIX

0

20

40

60

80

0 24 48 72

Immediate Release

Prolonged Release

[ng/ml]

H

In Vivo

ORAL ROUTE / PROLONGED RELEASESEMI SOLID LIPOPHILIC MATRIX

• Control of the release kinetics is obtained by the choice of the excipient and by its hydrophilic-lipophilic balance (HLB).

• Manufacturing process, excipient melting, drug substance dispersion in the molten mass and, pouring into hard gelatin capsules

ORAL ROUTESEMI SOLID MATRIX STABILISATION

Figure 5

Antiparkinson drug - 30°C/60%HRWithout stabilisation

0

25

50

75

100

0 4 8 12 16

Time (h)

Dru

g S

ub

stan

ce d

isso

lved

, %

initial1 month2 months3 months

Antiparkinson drug - 30°C/60%HRWith stabilisation (Servier's patent)

0

25

50

75

100

0 4 8 12 16

Time (h)

Dru

g S

ub

stan

ce d

isso

lved

, %

initial1 month2 months3 months

• Multiparticulate dosage form as small spherical reservoir beads (0.5 à1.5 mm diameter)

• Dissolution rate controlled by a semi-permeable membrane

ORAL ROUTE / PROLONGED RELEASEMICROPARTICLES

PROLONGED RELEASE MICROPARTICLES

Filters

Coating solution

Hot air

Semi permeable membrane

Drug substance + Excipients

In vitro dissolution rate of two different dosage forms

0

25

50

75

100

0 4 8 12 16 20 24

Time (h)

Dru

g Su

bsta

nce

diss

olve

d, %

Steady-state plasma concentrations of the two different dosage forms

010203040

5060708090

72 78 84 90 96 102

Time (h)

Pla

sma

conc

entr

atio

n (n

g/m

l)

ORAL ROUTESUSTAINED RELEASE MICROPARTICLES

IRIR

PPRR

IR 3 x dayIR 3 x day

PR 1 x dayPR 1 x day

ORAL ROUTE / DELAYED RELEASE

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14 16 18

Time (h)Time (h)

Drug Drug substance substance released (%)released (%)

ORAL ROUTE / DELAYED RELEASE

012345678

0 2 4 6 8 10 12 16 20 24 Time (h)

plasma concentration

(ng/ml)IR

DR

0

4

8

12

0 4 8 12 16 20 24Time (h)

ng/ml

ORAL ROUTE DELAYED AND PROLONGED RELEASE MICROPARTICLES

Plasma Concentration

In vitro dissolution rate

0

50

100

0 4 8 12 16

Time (h)Dru

g s

ub

stan

ce r

elea

sed

(%

)

ExploExploExploExplo

ProjecProjectt

ProjecProjectt

Preclinical Preclinical Stage AStage A

Preclinical Preclinical Stage AStage A Phase IPhase IPhase IPhase I Phase Phase

IIIIPhase Phase

IIII

Phase IIIPhase IIIPhase IIIPhase III NDANDANDANDA

Post Post NDANDAPost Post NDANDA

Preclinical Preclinical Stage BStage B

Preclinical Preclinical Stage BStage B

BioPharmaceutica

l Research

TOXICOADME

Salt Selection

Phase IFormulatio

n

PK Interaction

s

PB/PK

PK/PD

Up scaled Formulatio

n

Toxicological and kinetics Expertises

PopulationKinetic

Interspecies

metabolismcomparison

Pharmaceutical File

NewFormulation

Pharmaceutical

Support Regulatory

Affairs

Pharmacopoeia

Copy Analysis

POPULATION KINETIC

Time

Pla

sma

conc

entra

tion

CL creat

CL

renal impaired subjects

healthy subjects

Time

Pla

sm

a c

on

cen

trati

on

Bayesian feedback

PopulationPopulation Analysis Analysis

Time

pla

sma

con

cent

rati

on Population simulations((variabilityvariability))

Time

Pla

sma

conc

entra

tion

CL creat

CL

renal impaired subjects

healthy subjects

Time

Pla

sm

a c

on

cen

trati

on

Bayesian feedback

PopulationPopulation Analysis Analysis

Time

pla

sma

con

cent

rati

on Population simulations((variabilityvariability))

12

34

56

78

9

C L c r (L / h )

1 82 83 84 85 86 87 88 89 8

A g e (Y e a r s )

C L / F (L / h )

247

1 01 31 61 92 12 42 73 03 33 63 94 1

C l e a r a n c e E x t r a p o l a t i o nC l e a r a n c e E x t r a p o l a t i o n

• Therapeutic windowTherapeutic window• Relation conc. / effectsRelation conc. / effects• Side effectsSide effects• ToxicityToxicity• etc.etc.

• AbsorptionAbsorption• DistributionDistribution• MetabolismMetabolism• EliminationElimination• etc.etc.

• Status of the patient Status of the patient • Age, weightAge, weight• Stage of the illnessStage of the illness• Associated pathologiesAssociated pathologies• Associated treatmentsAssociated treatments• ComplianceCompliance• etc.etc.

• Administration routesAdministration routes• FormulationFormulation• Tolerance - addictionTolerance - addiction• Drug interactionsDrug interactions• Genetic Genetic PolymorphismPolymorphism• etc.etc.

Clinical Factors

Pharmacokinetics

OtherFactors

Activity - Toxicity

Clinical PKcs

Regimen

ExploExploExploExplo

ProjecProjectt

ProjecProjectt

Preclinical Preclinical Stage AStage A

Preclinical Preclinical Stage AStage A Phase IPhase IPhase IPhase I Phase Phase

IIIIPhase Phase

IIII

Phase IIIPhase IIIPhase IIIPhase III NDANDANDANDA

Post Post NDANDAPost Post NDANDA

Preclinical Preclinical Stage BStage B

Preclinical Preclinical Stage BStage B

BioPharmaceutica

l Research

TOXICOADME

Salt Selection

Phase IFormulatio

n

PK Interaction

s

PB/PK

PK/PD

Up scaled Formulatio

n

Toxicological and kinetics Expertises

PopulationKinetic

Interspecies

metabolismcomparison

Pharmaceutical File

NewFormulation

Pharmaceutical

Support Regulatory

Affairs

Pharmacopoeia

Copy Analysis

Pharmaceutical FilePharmaceutical File

COHERENCEAnalytical Methods

Impurities Degradation products

FORMULATION DESCRIPTIONDiluting and lubrification agents

Added excipients

REGULATORYCONSTRAINTS

% Qualification

PHARMACEUTICAL DEVELOPMENT

2 Definitions :

Drug substance = Active substance (New Chemical Entity or existing drug substance )

Drug product = medicinal product = Finished product (tablets, capsules, …)

BEGINNING OF PHARMACEUTICAL DEVELOPMENT (1)

Physicochemical properties of the new drug substance

solubility in water at different pH valueskinetics of dissolution as a function of

particle size........

Stability of the drug substance itselfstress conditions (acidic or basic pH, oxidation, temperature)

BEGINNING OF PHARMACEUTICAL DEVELOPMENT (2)

Choice of salt and cristalin form for development

- Solubility

- Stability

Chemical compatibility drug substance/excipients

Formulations for phase I

TYPES OF FORMULATION / ORAL ROUTE

Release of the drug substance

Immediate release (IR)

Modified release (MR)

prolonged release delayed release

IMMEDIATE RELEASE TABLET

Drug substance

Diluant (lactose, mannitol ....)

Binder (povidone,HPMC, maltodextrin ....)

Desintegrating agent (sodium starch glycolate,…)

Flowing agent (silica, talc ....)

Lubricant (magnesium stearate, stearic acid ....)

THE IDEAL FORMULATION (1)

Easy to manufacture, with a robust process giving always a quality product

Delivering the drug substance as needed according to its intrinsec pharmacokinetic properties (half-life, site of absorption......) and to the therapeutic needs :

prolonged release for a once-a-day formulation of a drug substance with a short half-life

quick Cmax to get an effect quickly lower Cmax to decrease side effects ......

Stable throughout the storage period chemical stability of the drug no evolution of the dissolution profile

INTERNATIONAL CONFERENCE OF HARMONISATION : I.C.H. PROCESS

Since 1990

The aim: to standardize the studies to be performed for the registration of a new product in the 3 main geographical areas :

• USA/Canada• Japon• European Union

3 topics• Safety (guidelines S) / Toxicology• Efficacy (guidelines E) / Clinical development• Quality (guidelines Q) / Pharmaceutical

development

I.C.H. PROCESSExample : Stability for zone II

Drug substance : 3 batches packaging representative of industrial packaging

Drug product : 3 batches (the size of 2 out of 3 is more than

1/10 that of industrial batches) packaging chosen for the market

Conditions : 25°C/60%RH throughout shelf-life 30°C/60%RH (65%RH in 2005) 1 year 40°C/75%RH 6 months

Time of analysis : 0, 3 months, 6 months, 9 months, 1 year,

18 months, 2 years, 3 years

MARKETING AUTHORISATION FILEDRUG SUBSTANCE

S.2 Preparation/synthesis

S.3 Characterisation (Physico-chemical properties,

structure and qualification of impurities)

S.4 Control of drug substance

S.7 Stability

MARKETING AUTHORISATION FILE DRUG PRODUCT

P.1 Description and composition

P.2 Process development/validation

P.3 Manufacturing process

P.4 Excipients

P.5 Control of drug product

P.7 Container closure system

P.8 Stability shelf-life and storage conditions

Change in Production SiteChange in Production SiteChange in Production SiteChange in Production Site

Improvment Improvment of of

Analytical Analytical TechnicsTechnics

Improvment Improvment of of

Analytical Analytical TechnicsTechnics

StabilityStability  New SpecificationsNew Specifications SolvantsSolvants

ImpuritiesImpurities

StabilityStability  New SpecificationsNew Specifications SolvantsSolvants

ImpuritiesImpurities

Up dating of the CMC FileUp dating of the CMC File

PHARMACOPEAPHARMACOPEAPHARMACOPEAPHARMACOPEA

1st WAY

SETTING THE SPECIFICATION OF THE ACTIVE PRINCIPLE

2nd WAY

Consensus within competitors Before patent issueMonopole situation

PHARMACOPEA FOR PERINDOPRIL

STRUCTURE Isomere S S S S S 31 isomeres as potentialimpurities < 0.1 %

TRACING IMPURITY  

N

CO - CH - NH - CH - C3H7

COOH(7a)

(3a)

(2)

(9) (11)

CH3 COOC2H5

N COOH

OCH3

NH

COOC2H5

HH

C3H7

H

H

1st pathway : Standard analysis criteria :

purity profil dissolution content

2nd pathway : Qualitative and Quantitative Analysis of the Formulation

COPIES AND COUNTERFEITS

How to distinguish Real from False ?How to distinguish Real from False ?

Suspicion of counterfeited Servier drugAnalysis of a whole truck content official ceremony to distroy the unlegal product

EX : SUSPECTED DRUG

ChinaChina

IndonesiaIndonesia

Suspicion of counterfeit but appeared to be parallel import through Australia then ???... Indonesia

MalteMalte

Suspicion of parallel import finally proved to be counterfeits

ExploExploExploExplo

ProjecProjectt

ProjecProjectt

Preclinical Preclinical Stage AStage A

Preclinical Preclinical Stage AStage A Phase IPhase IPhase IPhase I Phase Phase

IIIIPhase Phase

IIII

Phase IIIPhase IIIPhase IIIPhase III NDANDANDANDA

Post Post NDANDAPost Post NDANDA

Preclinical Preclinical Stage BStage B

Preclinical Preclinical Stage BStage B

BioPharmaceutica

l Research

TOXICOADME

Salt Selection

Phase IFormulatio

n

PK Interaction

s

PB/PK

PK/PD

Up scaled Formulatio

n

Toxicological and kinetics Expertises

PopulationKinetic

Interspecies

metabolismcomparison

Pharmaceutical File

NewFormulation

Pharmaceutical

Support Regulatory

Affairs

Pharmacopoeia

Copy Analysis

PHARMACEUTICAL PHARMACEUTICAL DEVELOPMENTDEVELOPMENT

Staff : 150Analytical methodsStability & Purity

analysisFormulation

Drug Delivery

Orléans VignatOrléans Vignat

TOXICOLOGYTOXICOLOGYGidyGidy

Staff : 109General Toxicology

Reproductive ToxicologyMutagenesis

CancerogenesisDrug Safety Research Drug Safety Research

Center GidyCenter Gidy Orléans Bel AirOrléans Bel Air

PHARMACOKINETICSPHARMACOKINETICS

LondonLondon

OrléansOrléans Staff : 136 (3 sites)Screening

ADME studiesPK/PD RelationshipsPopulation kinetics

Wexham, LondonWexham, London

CourbevoiCourbevoiee

OrléansOrléans

CourbevoieCourbevoie

BIOPHARMACYBIOPHARMACY