The Ideal DMPK Profile
versus Lead Optimization
Clinical DMPK Profile
High oral bioavailability:
Half-life between 12 and 24 hr:
Multiple elimination pathways:
No reactive metabolites:
No human-specific metabolites:
No inhibition of CYP450 enzymes:
No induction of CYP enzymes:
Rationale
Low inter-subject variability/ cost of goods
QD dosing/ acceptable accumulation
Drug-drug interactions (DDI) less likely
Avoid safety issues/ idiosyncratic AEs
Simplifies safety program & risk assessment
Drug unlikely to cause DDIs
Avoid autoinduction or DDIs
Drug Safety DMPK Profile
Good PK with developable form:
Acceptable exposure multiples:
Stable and predictable exposure:
Clean in AMES test:
Crystalline form - reduced bioavailability?
Human risk assessment
Reliably target appropriate exposure
Avoid mutagens
Discovery DMPK In Vitro Assays
Assay
CYP 450 Inhibition:
CYP 450 Profiling:
Rat liver slice - induction:
hPXR :
Hepatocyte clearance:
Inter-species hepatocyte met ID :
Plasma stability:
Plasma protein binding:
Mock hERG drug assay:
Caco-2:
Rationale
Avoid drug-drug interactions (DDI)?
Avoid Polymorphism? Avoid DDI?
Predict in vivo rat enzyme induction.
Predict CYP 3A4 induction in humans.
Predict human metabolic rate.
Look for human-specific metabolites.
Ex vivo degradation?
Normalize exposure based on ‘free’ drug
Confirm actual concentration.
Predict human absorption potential.
Discovery DMPK In Vivo Studies
Study
Full” PK (IV & PO):
Single-rising dose:
14-Day Rat multiple dose:
Rationale
Predict human PK
Adequate exposure for safety testing
Steady-state; tumorigenic induction
‘Hot’ PK (3H-SCH) :
Absorption and circulating metabolites
Metabolite Pathway Elucidation:
Identify metabolites in ‘safety’ species
Mass Balance of 3H-SCH:
Avoid unusual retention of metabolites
Melanin Binding (LE rats):
Assess phototoxicity potential
PK/PD:
Developable form acceptability:
Estimate efficacious drug exposure
Adequate exposure for safety testing
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics (PK)
Pharmacodynamics (PD)
Concentration vs Time
Effect vs Concentration
PK/PD
Effect vs Time
Assumption: The magnitude of the desired effect (or side
effect) is a function of the drug concentration at the site of
action
PK-PD relationship
Drug excretion
(Metabolism-Elimination)
Drug at
Absorption
Site
Drug in
Tissues
(Distribution)
Pharmacokinetics
PK
PD
Drug at
Drug at
Effect
Effect
SiteSite
Response!!
Pharmacodynamics
What your body does to the drug
What the drug does to your body
Different potency
in different species
The PK-PD relationship
The test compound has a full effect at the dose of 10 mg/kg po
Pharmacological
effect
16
cutoff
800
14
700
12
600
10
500
8
400
6
300
4
200
2
100
0
0
0 30 60
120
180
240
360
Plasma
level
ng/ml
Veh
10 mpk, po
Time (min)
At 10 mg/kg po the temporal profile of the plasma level
and the pharmacological activity profile are similar
Safety and preclinical toxicology
Safety
Effect on the principal physiological system
(cardiovascular, renal, nervous, etc).
Safety pharmacology
Precinical
toxicology
To
1.
2.
3.
4.
5.
establish :
safe dose
MTD (maximum tolerated dose)
terapeutic window
target organs
Reversibility of toxicity
Toxic effects could mechanism-based or
compound-based.
Preclinical toxicology
•Acute toxicity profile
•Chronic toxicity profile
• 14 days toxicity test in one rodent and one non-rodent
species before use in man.
• 3 months study read out at 28 days
• longer studies (12 & 24 month)
• Mutagenicity tests in vitro and in vivo
What a therapeutic window is?
Therapeutic
effect
Tolerability
Toxicity
Sedation
Ansiolitic
effect
Respiratory
depression
P2Y12 antagonists
Therapeutic index evaluation
(van Giezen and Humphries Semin Thrombosis Hemost 2005)
It is possible to obtain a clear separation between antithrombotic and bleeding effects
Reasons for Failure in Development
Toxicity (22%)
Lack of Efficacy (31%)
Market Reasons (6%)
Poor Biopharmaceutical (PK) Properties (41%)
Moving from Animals to Man
1.
2.
3.
Humans and animals have different biochemistry, physiology and
anatomy
Predictions of a drug’s PK profile in humans using animal PK data
must account for these differences
Allometric scaling is used to predict differences based only on size.
•
•
•
•
The relationship of some PK parameters across species can be correlated with
body weight.
One can determine an empirical relationship log PK parameters and log Body
Weight
These parameters can be used to extrapolate PK parameters in humans when
parameters have been determined in lower species (mouse, rat, dog, monkey,
etc.)
The relationship is not always predictive, but it can often give a good estimate.
Summary
The information collected in ADME
and DMPK study are necessary to establish
the dose that will be used in human
Questions??
R&D process for a new drug
CANDIDATE
POC
Exploratory
development
Developpability
Fase 0 or
Preclinical
development
Safety
Fase I (A
and B)
Full
development
Therapeutic efficacy
Fase II
Study in the
patient
D
R
U
G
Pre-marketing
Fase III
Study in the
patient
Registration
Fase IV
Post marketing
Surveillance
Formulation study
• Pharmaceutical form: tablet , capsule, cream, injection, etc
•To achieve the best effect is necessary to identify not only the
best form but also the most suitable formulation.
Example of composition of a tablet:
•Active principle, filler, binder,
lubricant, disintegrant, surfactant.
Objectives of Clinical Trials
• Phase I: First in man  safety e tolerability
• Phase II: First in patient
IIa  safety and tolerability
IIb dose, dosage form
• Phase III: Value (is better than existing treatments)
• Post marketing surveillance or Phase IV : Monitor the
drug in the real clinical setting
Clinical trials
Uncontrolled
Controlled
Randomized
Open or blind
Sequential or cross-over