NON CLINICAL DEVELOPMENT OF DRUG NON CLINICAL DEVELOPMENT OF DRUG SPECIALITIES SPECIALITIES ________________________ ________________________ Bernard MARCHAND Bernard MARCHAND
Jan 23, 2016
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