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Phase I
in clinical drug development
M2 Pharmacocinétique
7 février 2012
Philippe Grosjean
Sanofi R&D
Clinical Sciences and Operations
| 1
New drug investigations in human
● Objectives of the clinical investigations of drugs or
devices in human
● Therapeutic (efficacy and adverse events)
● Pharmacodynamic (including the mechanism of action)
● Pharmacokinetics (ADME)
| 2
The Drug Development Process
RESEARCH
2 years
RESEARCH
INTO
CHEMICAL
STARTING
POINTS
• Conception
• Target selection
• Test Development
• Synthesis
SCREENING
(+ High Throughput
Screening)
DEVELOPMENT
1 to 2 years
1 to 2 years
OPTIMIZATION
PRECLINICAL
EVALUATION
IN VITRO AND
IN ANIMAL
• Intrinsic activity • Chemical
Development
• Selectivity
• Oral absorption • General
Pharmacology
• Duration of
• Analytical
action
Methods
• Efficacy in
relevant animal • Stability
models
• Safety
• Toxicity
• Metabolism and
6 to 8 years
50,000 to 500,000
molecules
1 year
Contin.
P
R
PREPARATION
PHASE I
PHASE II
PHASE III
Determination
of the optimal
dose
10
R
M
3
A
MARKETING
O
D
and
SUBMISSION
Confirmation
of the
of a
therapeutic
effect and NEW DRUG
tolerance
APPLICATION
Tolerance
Biological
and
activity and
pharmaco- research of a
therapeutic
kinetics
effect
P H A
30
LIFE
CLINICAL EVALUATION
IN MAN
Pharmacokinetics
• Formulation
Active Molecules
(lead compounds)
BIRTH
U
C
LIFE
T
CYCLE
I
O
DOSSIER
LCM
MANAGEMENT
N
C
O
V
I
G
I
L
A
N
C
1
| 3
E
Economic aspects: development costs
| 4
Reason for development discontinuation
| 5
Different phases of clinical development
Phases
Objectives
I
Safety (pharmacovigilance), tolerability, pharmacokinetics, and
pharmacodynamics of a drug (except oncology and growth factor…)
in healthy subjects
Assess dosing requirements (how much drug should be given) in
subgroups of patients.
Assess efficacy (how well the drug works at the prescribed dose(s)).
Dose-effect relationship
IIa
IIb
III
Assess (confirm) the therapeutic efficacy, the tolerance compared
to reference drug at a larger scale in the target population
IIIb, IV
Post-marketing studies (tolerability, extension of indication, other
populations, regulatory requests…)
| 6
Phases of development
Pre-Clinical
Discovery
●
Pre-clinical
Phase
I
Phase
IIa
Phase
IIb
Phase
IIIa
Clinical Dev.
Phase
IIIb
Approval
Phase
IV
Launch
Phase I
● First in Man
• Clinical trials in healthy subjects first (6 to 100 subjects)
• Voluntary participation
• Compensation related to study participation
• No direct medical benefit
● Numerous objectives
• Tolerance and its relationship with the dose
• Pharmacokinetic studies
• Later phases support
• Interactions
• Special populations
• Pharmacodynamic
● Rapid studies (several months to complete)
| 7
Clinical development plan
● Summarizes the rationale, the objectives, the strategy of
investigational product development
● Study needs
● Study links – relationship - chronology
● Go/no go criteria
● Plan discussed with the Health Authorities at the beginning
of development
● Regular meetings during the course of development
● At specific times (e.g. end of phase II…)
| 8
Schematic presentation of a clinical plan
Carcinogenicity
Tox 1
Tox 6
Tox 3
New
formulation
Metabolism
Interaction
PK 1
Food
effect
FIM
RD
Interaction
PK 2
PDyn
Registration
support
Efficacy 1
Dose finding
endpoint y
Efficacy 2
Dose finding
endpoint x
...
Y1
Y2
Y3
| 9
Regulatory environment (1/2)
●
●
Strict international regulatory environment
● Declaration of Helsinki and its revisions (1964)
● ICH recommendations
● Good Clinical Practices
Country-dependent regulations (e. g. Ethics committees, IRB…)
● USA : Code of Federal Regulation of the FDA (Food and Drug
Administration)
● Europe : European directive (2001, France 2004)
● France : Loi « Huriet » (modifiée à la suite de la Directive Européenne sur
les Essais cliniques) : autorisation des lieux de recherches, consentement,
Comités de Protection des Personnes, fichier national des volontaires
sains...
• La loi distingue deux grandes catégories de recherches biomédicales
• Celles dont on attend un bénéfice individuel direct et immédiat, pour la
personne (malade) qui s’y prête ou une partie des personnes
concernées.
• Celles dénommées sans bénéfice individuel direct où aucune des
personnes ne peut tirer un bénéfice personnel et immédiat pour sa santé
| 10
Regulatory environment (2/2)
●
The clinical development is conditioned by a scientific and technical
dossier including animal experimental data within a precise regulatory and
legal framework
●
Before FIM: toxicology pre-requisites, characterization of the compound
(part of the investigator’s brochure…)
●
Trials conduct: protection of the subjets, choice of clinical centers,
methodology (statistics, reference, placebo, design…)
●
Number of trials and number of subjects needed
●
Information presented in a standard dossier (CTA clinical trial application /
investigational medicinal product dossier EUR in force in France since
August 2006) or IND investigational new drug (US)
| 11
Toxicology pre-requisites : phases I, II (Europe)
Study Type
Parameters assessed
Pharmacology
Vital functions (respiratory system,
cardiovascular syste, CNS…)
Toxicokinetic and
pharmacokinétic
Absorption,distribution, metabolism, excretion
Acute and chronic toxicity
2 species (rodent, non-rodent)
Genotoxicity
Mutations, chromosomal aberrations
Reproduction
Male fertility (not required for healthy male
subjects inclusion), female fertility,
embryogenesis, post and peri-natal abnormalities
Local tolerance
If needed (eg : topic, IV…)
| 12
Toxicology pre-requisites: phases I ,II (US, EU)
Planned duration of clinical trial
Single dose
Up to 2 weeks
Up to 1 month
Up to 3 months
More than 3 months
Minimum duration of toxicity studies
Rodent
Non-rodent
2-4 weeks
2-4 weeks
3 months
6 months
6 months
2 weeks
2 weeks
3 months
3 months
chronic
| 13
Choice of dose in First-in-Man
● FDA approach
● Maximum recommended starting dose (MRSD)
• Example
● Allometric scaling
● Predicted human clearance
• Example
● MABEL
● Pharmacology rather than toxicology
| 14
Take into account animal toxicity findings
●
Monitorability animal findings
●
●
●
●
●
●
●
Laboratory
ECG
Exploratory parameters
Histopathology
Severity of findings
Reversibility
Type of findings
● Body systems
● Death
●
●
●
Differences between species / gender
Knowledge of the therapeutic class
Definition of the No Observable Adverse Effect Level (NOAEL)
| 15
Animal PK
•
Rat defined as the most sensitive species based on
tolerability in 1-month toxicity studies in rat and dog
Species Dose
(mg/kg/day)
NOAEL
Cmax (ng/mL)
AUC (ng.h/mL)
Male
Female
Male
Female
Dog
3
1750
1670
15000
14000
Rat
3
529
760
1430
8570
10
6670
6190
87600
72400
10
2140
3290
6620
39000
First toxic Dog
dose
Rat
• NOAEL: No observable adverse effect level
| 16
First dose proposal for FIM
Toxicology data: FDA approach
●
Maximum Recommended Starting Dose (MRSD)
● Human Equivalent Dose: HED= NOAEL x BSA-CF
• NOAELRAT and DOG: 3 mg/kg/day (or most sensitive species)
• BSA-CF: body surface area converting factor: 0.162 for rat, 0.541 for dog
• HEDdog = 1.62 mg/kg
• HEDrat = 0.49 mg/kg = lowest HED
● MRSD (mg) = HEDrat x HBW x SF-1 Safety factor (SF)
• SF = 10 (default)
• HBW: human body weight = 60 kg (default)
MRSD is (3 x 0.162 x 60)/10 = 2.9 mg
| 17
Prediction of Human Clearance
Allometric Scaling (Mahmood and Balian Method)
Cl = a*(W)b
Human Clpred
Rabbit
Dog
Rat
• Predicted CLhuman = 6.6 L/h
• Exponent of simple allometric equation (b=0.515) not included in 0.55 to
0.70 (no other correction needed e.g. brain weight…)
ª Simple allometric approach could lead to underestimation
| 18
First dose proposal for FIM
Toxicology data: allometric approach
●
●
PK based approach
FIM Dose (mg) = Clhuman x AUC NOAELrat / F x SF
● Clhuman , lowest predicted clearance, 6.6 L/h
● AUCNOAEL, male rat, 1.43 mg.h/L
● AUCNOAEL, female rat, 8.57 mg.h/L
● Safety factor (SF) = 10 (default)
● Bioavailability F = 1 (default)
Proposed First-in-man dose : (6.6 x 1.43) / (1 x 10) = 0.94 mg
based on male rat (based on female rat = 5.7 mg)
| 19
First dose summary
species BSA / Dose-based (FDA) CLPred /PK-based
Toxicology
approach
Rat
2.9 mg
0.94 – 5.7 mg
Recommendation to start with 1 mg
| 20
Considerations of the choice of the top dose
●
Dose range should not significantly exceed the exposure at FTD in F rat
(6.6 mg.h/mL)
●
Dose/BSA approach
● Human Equivalent Dose (mg) = FTD (mg/kg) x BSA-CF
● In rat, FTD is 10 mg/kg, HED = 10 x 0.162 = 1.62 mg/kg
• total dose = 97.2 mg (hbw 60 kg)
● In dog, FTD is 10 mg/kg, HED = 10 x 0.541 = 5.41 mg/kg
• total dose = 324.6 mg (hbw 60 kg)
HED: lowest corresponding HED is 97.2 mg
| 21
Considerations of the choice of the top dose
●
PK-based approach
● Human Equivalent Dose(mg) = Clhuman (L/h) x AUCFirst toxic dose(mg.h/L)
● Clhuman, lowest predicted clearance = 6.6 L/h
● AUCFirst toxic dose
• In male rat, FTD is 10 mg/kg, corresponding AUC is 6.6 mg.h/L
• 6.6 x 6.6L/h = 43.6 mg
• In female rat, FTD is 10 mg/kg, corresponding AUC is 39 mg.h/L
• 39 x 6.6 = 257.4 mg
• In dog, FTD is 10 mg/kg, corresponding AUC is 72.4 mg.h/L
• 72.4 x 6.6L/h = 477.8 mg
HED: lowest corresponding HED is 43.6 mg
Top dose capped by exposure < 6.6 mg.h/mL
Consider Cmax when intravenous route
| 22
Dose proposal for FIM
First and top doses proposal
BSA / Dosebased
CLPred /PK-based
Proposal
Starting
Dose
2.9 mg
0.94 mg
1 mg
Top Dose
97.2 mg
43.6 mg
80 mg
Human equivalent dose
Top dose 80 mg if exposure < 6.6 mg.h/mL
| 23
Dose proposal for FIM: doses range proposal
Dose
Dose (mg)
Escalation rate
ratio
HED
Starting dose
1
-
NOAEL/10 Male (M) rat (3 mg/kg) (PredCL)
2
2.5
2.5
3
5
2
4
10
2
≈ NOAEL M rat (3 mg/kg) (PredCL)
5
20
2
< FTD/2 M rat (10 mg/kg) (PredCL)
6
40
2
< FTD M rat (10 mg/kg) (PredCL)
80 *
2
1
7
Top dose
If AUC<FTD M rat (10mg/kg/day) and
< NOAEL Female (F) rat (3mg/kg/day)
* 80 mg or earlier with exposure <6.6 mg.h/mL
| 24
Pharmacological / biological effects (not only
adverse effects) should guide the starting dose
When the methods of calculation (e.g. NOAEL, MABEL) give different
estimations of the first dose in man, the lowest value should be used.
| 25
The main challenge… selection of a pertinent
biological parameter for calculating the MABEL
●
Preclinical efficacy or activity parameter in vivo
● Lowest dose showing a significant shift in efficacy or activity
● Then calculate the HED
●
Receptor binding on human cells
● Concentration - percent occupancy
• For agonists, choose the concentration with low percent occupancy
(10%)
• For antagonists, higher percent occupancy may be reasonable
● Use animal PK data to project concentrations in humans
●
In vitro human cell responses
● Concentration – response
● Use animal PK data to project concentrations in humans
●
… apply a safety factor (currently not specified)
| 26
Methodology of clinical trials
● Placebo
● Neutral substance that substitutes a drug in order to control or
suscitate the psychologic effects linked to drug intake
● Essential for the use of blinding procedures
● Allows to answer the question, is the new treatment efficacious?
● Blinding
● Indicate that the nature of treatment is not known
● Allows to reduce the bias in clinical trials, in particular to
evidence the placebo effect
● Single blind: only the subjects ignore the treatment received
● Double-blind: both the subjects and the investigator(s) ignore
the treatment received… and actually the sponsor as well
| 27
Parallel groups
Screening
W-3
Week1
W2
W3
W4
W5
W6
W7
Follow-up
W8
R
R
ED
Dose 7 optional
+ PK Dose 5
R
R
ED
Dose 6
+ PK Dose 4
R
R
ED
Dose 5
+ PK Dose 3
R
R
ED
Dose 4
+ PK Dose 2
R
R
ED
Dose 3
+ PK Dose 1
R
R
R
R
D1
n=4
Dose 2
ED
n=4
Dose 1 (8 subjects : 6V + 2 P)
D2
do
do
sin
sin
g
g
D7
R
Randomization
ED
decision of dose
escalation based on
tolerability profile of
|
dose n-1
28
Parallel groups
● Pros
● Simple protocol
● Limits the study duration for a subject
● No carry-over effect, no period effect
● Cons
● Increases the number of subjects
● No assessments of the intra-individual variability
| 29
Cross-over
Sequences
Product A
A-B
B-A
Sequences
A-E-D-C
B-A-E-D
C-B-A-E
D-C-B-A
E-D-C-B
Period 1
Product B
A
Wash out
Incomplete sequences
B
C
D
E
Period 1
Sequence BA
Period 2
Period 2
Period 3
Period 4
1-sequence
| 30
Cross-over
● Pros
● Decreases the number of subjects
● Assess the intra-individual variability
● Cons
● Increases the duration of study (per subject)
● Period effect
● Carry-over effect
| 31
First in Man – Single dose
●
Objectives
● Assess the tolerability and safety after single dose
● Define a maximum tolerated dose (MTD) or maximum adminsitered
dose (MAD)
● Define the PK profile
●
Design
●
●
●
●
●
Double-blind, placebo controlled, parallel groups
single dose
8 subjects per group (dose) with 2 placebo and 6 verum
Usually, 5 to 7 ascending doses tested
Assessments
● Adverse events, clinical laboratory, ECG, vital signs, other safety
parameters, PD, biomarkers
● PK
| 32
First in Man – Repeated dose
● Objectives
●
● Assess the tolerability and safety after repeated doses
● Define a MTD or MAD
● Define the PK profile
• Rac
Design
●
●
●
●
Double-blind, placebo controlled, parallel groups
7 to 14 days of administration (QD, or BID)
12 subjects per group (dose) with 3 placebo and 9 verum
Usually, 2 to 4 ascending doses tested
● Assessments
● Adverse events, clinical laboratory, ECG, vital signs, other
safety parameters, PD, biomarkers
● PK
| 33
Other phase I studies with safety/PD objective(s)
● DALA (Drug of abuse liability assessment)
● Part of the Registration Dossier for CNS acting drugs (primary or
secondary effects)
• Based on behavioral effects in animals
• Dependence, overdose, and drug abuse liability potential
● TQT (Thorough QT study )
● Assess effect of the investigational product on cardiac
repolarization
● Pharmacodynamic
●
●
●
●
Mechanism of action, biomarker
Safety parameters
Challenge tests
Other
● Other, product-dependent
| 34
PK studies
●
●
Numerous studies with a PK objective can be conducted during an investigational product
development
●
They occur at different stages of the drug development
Type of studies include
●
●
●
●
Drug-drug interactions
• Based on in vitro metabolic profile (CYP, transporters)
• Compound on other drugs’ PK profile
• Other drugs on the compound’s PK profile
• Food (includes alcohol, fruit juices, high-fat meals, high-carbohydrate meals…)
Metabolism
Bioavailability
• Bioequivalence
• Absolute
• Relative
• Formulation comparisons
Specific populations
• Hepatic impairment
• Renal impairment
• Elderly
• Children
| 35
PK to support development (1/5)
●
Excretion balance and metabolism study
● Further development of drugs requires greater knowledge of the
metabolism and excretion in human.
• To determine the excretion balance and systemic exposure of radioactivity
after oral administration of [14C]-drug;
• To determine the PK of the drug and its contribution to overall exposure of
radioactivity;
• To determine the metabolic pathways of the drug and identify the chemical
structures of the main metabolites
● Based upon the results, PK studies in patients with renal and/or hepatic
impairments will be performed subsequently
● Identification of major metabolites
● N = 4 to 6
● Collection of blood, urine, feces, expired CO2
● Usually long collections periods >8 days (t1/2z)
| 36
PK to support development (2/5)
●
Interaction with CYP3A4 substrate (midazolam)
● Effect of the IP on a drug’s PK which is a substrate of CYP3A4
● Depends on in vitro in human liver microsomes investigations
● Midazolam is exclusively metabolized by CYP3A4/3A5; after oral
administration, its clearance reflects combined intestinal and hepatic
CYP3A activity.
● The aim of this study is to assess the effect of a repeated administration
of the IP on the pharmacokinetic profile of a single dose of midazolam, in
healthy male and female subjects
● Classification of CYP3A inhibitors
• a single oral dose of midazolam allows discrimination between strong (≥ 5fold increase in midazolam plasma AUC values), moderate (2 to 5-fold
increase) and weak inhibitors (1.25 to 2-fold increase)
● Cross-over
● N = 12
| 37
PK to support development (3/5)
● Interaction with CYP3A inhibitor (ketoconazole)
● Effect of a potent CYP3A inhibitor on the PK of the IP
● Based on invitro studies that showed that the IP is metabolized
by cytochrome P450 3A (CYP3A) isoenzyme.
● Ketoconazole is a well-known potent CYP3A4 inhibitor
• Widely used as a reference inhibitor to test in vivo the potential
effect of CYP3A inhibition on drugs being a substrate for this
enzyme
● The aim of this study is to assess the effect of a repeated
ketoconazole administration on the pharmacokinetic profile of
a single oral dose of the IP, in healthy male subjects
• Cross-over
• N = 12
| 38
PK to support development (4/5)
●
Cocktail interaction study
● When preclinical data suggest that an IP could have an impact on several subtypes
of the cytochrome P450, potential drug-drug interactions, using a CYP probe
cocktail (1A2, 2C9, 2C19, 2D6 and 3A4) can be investigated
• Probes showed identical PK when administered separately or when combined
together (cocktail)
• Bioequivalence (cocktail versus each probe drug alone) was demonstrated for both
Cmax and AUClast
• Combined administration of the five probes proved to be well tolerated.
● Global approach enables the testing of several hypotheses in the same study, in a
limited number of healthy subjects
● Assess the effect of the IP on the pharmacokinetics of each cocktail probe
• CYP2C9, 2C19 and 2D6 poor metabolizers (PM) will be excluded of this study
• 2C9 : warfarin: 10 mg single dose
• 1A2 : caffeine: 100 mg single dose
• 2C19 : omeprazole: 20 mg single-dose
• 2D6 : metoprolol: 100 mg single dose
• 3A4 : midazolam: 0.03 mg/kg single dose, leading to a 2 mg dose in this study
population
● Cross-over
● N = 20
| 39
PK to support development (5/5)
● Interaction with food – case study
● Safety Results: IP at 200 mg single dose was well tolerated in healthy
subjects whatever the condition of administration (fasted or fed
[standardized high-fat breakfast])
● As compared to fasted administration, after a single oral dose of 200
mg administered following a high-fat food intake, Cmax and AUC
strongly increase by 73.8-fold and 41.5-fold, respectively.
| 40
Transition to phase II
● Early phase I studies provided
● Safety and tolerability data
• Wide dose range (SD, RD)
● Pharmacokinetic data
• Drug-drug interactions (assess most co-prescribed drugs)
● Pharmacodynamic data
● Bridging studies
• Match safety/PD in target population
● Based on these data
Early
Phase I
data
● Phase II doses are selected
• Safety ratio
• Activity or efficacy / exposure ratio
● Treatment duration is defined according to the disease
● Phase I continues to support registration
| 41
Merci de votre attention !
| 42