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