Presentazione di PowerPoint

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The Ideal DMPK Profile versus Lead Optimization
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Discovery DMPK In Vitro Assays
Assay
Rationale
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
drug Confirm actual concentration. Predict human
absorption potential.
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Discovery DMPK In Vivo Studies
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Pharmacokinetics and Pharmacodynamics
Assumption The magnitude of the desired effect
(or side effect) is a function of the drug
concentration at the site of action
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PK-PD relationship
PK What your body does to the drug PD
What the drug does to your body
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Different potency in different species
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The PK-PD relationship
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Safety and preclinical toxicology
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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

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What a therapeutic window is?
Toxicity
Respiratory depression
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Therapeutic index evaluation
P2Y12 antagonists
(van Giezen and Humphries Semin Thrombosis Hemost
2005)
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Reasons for Failure in Development
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Moving from Animals to Man

• Humans and animals have different biochemistry,
  physiology and anatomy
• Predictions of a drugs 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.

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Summary
The information collected in ADME and DMPK study
are necessary to establish the dose that will be
used in human
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Questions??
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RD process for a new drug
CANDIDATE
POC
DRUG
Exploratory development
Full development
Safety
Developpability
Therapeutic efficacy
Fase 0 or Preclinical development
Fase II Study in the patient
Fase III Study in the patient
Fase I (A and B)
Fase IV Post marketing Surveillance
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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.

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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

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Clinical trials
Uncontrolled Controlled Randomized Open or
blind Sequential or cross-over