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Clinical DMPK Profile. Rationale. 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:. Low inter-subject variability/ cost of goods - PowerPoint PPT Presentation
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The Ideal DMPK Profileversus Lead Optimization
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:
Low inter-subject variability/ cost of goodsQD dosing/ acceptable accumulationDrug-drug interactions (DDI) less likelyAvoid safety issues/ idiosyncratic AEsSimplifies safety program & risk assessmentDrug unlikely to cause DDIsAvoid autoinduction or DDIs
RationaleClinical DMPK Profile
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 assessmentReliably target appropriate exposureAvoid mutagens
Discovery DMPK In Vitro Assays
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:
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’ drugConfirm actual concentration.
Predict human absorption potential.
Assay Rationale
Discovery DMPK In Vivo Studies
Study Rationale
Full” PK (IV & PO): Predict human PK
Single-rising dose: Adequate exposure for safety testing
14-Day Rat multiple dose: 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: Estimate efficacious drug exposure
Developable form acceptability: Adequate exposure for safety testing
Pharmacodynamics (PD)
Effect vs Concentration
Pharmacokinetics (PK)
Concentration vs Time
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
Pharmacokinetics and Pharmacodynamics
PK-PD relationship
PK What your body does to the drug
PD What the drug does to your body
Drug at Absorption
Site
Drug at Effect Site
Response!!
PharmacodynamicsPharmacokinetics
Drug at Effect Site
Drug in Tissues(Distribution)
Drug excretion(Metabolism-Elimination)
Different potency in different species
The PK-PD relationship
Time (min)
0 30 60 120 180 240 360
Pharmacologicaleffect
0
2
4
6
8
10
12
14
16
Veh10 mpk, po
cutoff
The test compound has a full effect at the dose of 10 mg/kg po
800
700
600
500
100
300
200
400
0
Plasmalevel
At 10 mg/kg po the temporal profile of the plasma leveland the pharmacological activity profile are similar
ng/ml
Safety and preclinical toxicology
SafetyEffect on the principal physiological system (cardiovascular, renal, nervous, etc).
Precinical toxicology
To establish :1. safe dose 2. MTD (maximum tolerated dose)3. terapeutic window4. target organs5. Reversibility of toxicity
Safety pharmacology
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
Respiratorydepression
Ansiolitic effect
Therapeuticeffect
Sedation
Tolerability Toxicity
What a therapeutic window is?
Therapeutic index evaluation
(van Giezen and Humphries Semin Thrombosis Hemost 2005)
It is possible to obtain a clear separation between antithrombotic and bleeding effects
P2Y12 antagonists
Reasons for Failure in Development
Toxicity (22%)
Lack of Efficacy (31%)
Market Reasons (6%)
Poor Biopharmaceutical (PK) Properties (41%)
Moving from Animals to Man1. Humans and animals have different biochemistry, physiology and
anatomy
2. Predictions of a drug’s PK profile in humans using animal PK data must account for these differences
3. 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
Exploratorydevelopment
Fulldevelopment
DRUG
CANDIDATE POC
Fase IVPost marketing
Surveillance
Fase I (A and B)
Safety
Fase II Study in the
patient
Fase III Study in the
patient
Therapeutic efficacy
Registration
Pre-marketing
Fase 0 orPreclinical development
Developpability
Formulation studyFormulation study
Example of composition of a tablet:
•Active principle, filler, binder,
lubricant, disintegrant, surfactant.
• 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.
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