Transcript Objectives of the presentation

ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
Rationale for the effective use of
pharmacokinetics and
pharmacodynamics in drug
development
Update: 09/10//2010
P.L. Toutain
1
Objective of the presentation
• To show non-kineticists that PK can be a
very useful tool to document drug safety
and efficacy
• To understand the meaning and utility of the
main PK parameters
2
PHARMACOLOGY
Pharmacokinetics
Action of animal on drug
Clinical pharmacology
Study of drug in a
clinical context
Pharmacodynamics
Action of drug on animal
3
Clinical trials
vs.
PK/PD trials
4
Dose titration
Dose
Response
Black box
PK/PD
PK
PD
Response
surrogate
Dose
Plasma
concentration
5
Dose effect vs. concentration effect
relationship
EFFECT
External dose
DOSE
EFFECT
Internal dose
AUC = (Dose/Cl)
Less variance must be expected in the AUC/effect
than in the dose/effect relationship
6
Acute toxicity of anticancer drugs
human versus mouse
AUC Ratio
Internal dose
Frequency
Dose Ratio
External dose
14
14
12
12
10
10
8
8
6
6
4
4
2
2
0
0-1
0.4-0.6
0.6-1.2
2.0-3.0
>4
0
0-1
0.4-0.6
0.6-1.2
2.0-3.0
>4
8
Digoxin levels in toxic and
nontoxic patients
Non toxic (131)
Toxic (48)
* From smith TW and haber E. J clin invest 1970;49:2377-86.
9
The concentration principle in
drug development:
Extrapolations
• From in vitro to in vivo
• From experimental to target species
10
PK/PD: in vitro vs. in vivo
In vivo
Plasma
concentration
Body
Response
Extrapolation
in vitro  in vivo
In vitro
Medium
concentration
effet
Test system
11
The concentration principle
in drug development:
mechanistic approach
13
PK/PD: mechanistic approach
PK/PD
PK
PD
Response
Dose
Plasma
concentration
Dose
Response
Plasma
concentration
Drug receptor
interaction
Transduction
System specificity
Drug specificity, affinity &
intrinsic efficacy
14
Dose vs. plasma concentration
profile as independent variable
Dose
Mass
(no biological
information)
Dose
X
F%
Clearance
Time
Concentration profile
(biological information)
18
PK vs. PD variability
i.e. the 2 main sources of variability
19
PK and PD variability
PK
Dose
PD
BODY
Receptor
Effect
Plasma
concentration
well documented
–
–
–
–
–
species
food
age
sex
diseases
Generally ignored
but usually more
pronounced than PK
variabilities (for a given
species)
21
PK/PD variability for antiinflammatory drugs
Coefficient of variation (%)
PK
PD
Clearance Vss
EC50
EC50
antipyretic anti-inflammatory
Nimesulide
Tolfenamic Ac.
Prednisolone
T. Haake, 1997
17
28
12
20
9.5
15
49
47
62
48
49
22
Definition of the main
pharmacodynamic drug properties
• Efficacy
– Drug action, drug effect, drug response
– efficiency
• Potency
– Power
• Sensitivity
• Selectivity
• Specificity
23
The 3 structural parameters of the
dose-effect relationship
1
Emax 1
slope
ED50
Emax
2
2
Emax 2
1
1
2
shallow
steep
ED501 ED502
Efficacy
Potency
Sensitivity
Range of useful
concentrations
Selectivity
24
Efficacy vs. potency and selectivity
• Efficacy, potency and
selectivity
Effect
A
therapeutic effect
side effect
B
100
80
Concentration
A more potent than B
A = B for efficacy
25
B is preferable to A in a clinical context for its selectivity
PK/PD variabilitiy
• Consequence for dosage adjustment
PK
Dose
PD
BODY
Receptor
Effect
Plasma
concentration
Kidney function
Liver function
...
Clinical covariables
• disease severity or duration
• pathogens susceptibility
Population approach
26
Kinetic population vs. classical approach
Classical
Population
• Subjects
Few (healthy)
Many (patient)
• Location of study
laboratory
hospital
• Sampling
intensive
sparse
• Subject homogeneity
yes
no
• Controlled variable
yes
no (but documented)
• Inference space
narrow
large
28
What is the usefulness of PK
Drug discovery and
development
Drug submission
A scientific tool
R&D
Scientific critical mass
of the company
Can be very sophisticated
Drug prescription
A requirement for
regulatory affairs
Drug monitoring
Guidelines
Human medicine
Very basic
29
Usefulness of PK
1-Drug prescription
30
Drug candidates for Therapeutic
Drug Monitoring (TDM)
• Low therapeutic index
• No physiologic or therapeutic endpoints to guide
dosage
• Pharmacokinetics vary widely between
individuals
• Need to monitor adherence ?
31
Effect of adherence rate on outcome in
HIV infected patients
VIROLOGIC FAILURE RATE
(%)
80
60
40
20
0
≥ 95%
80% - 94%
< 80%
ADHERENCE RATE
From: Paterson DL, et al. Ann Intern Med 2000;133:21-30.
32
Usefulness of PK
2-Drug discovery
33
Drug discovery and PK
• The success rate of New Chemical Entities
(NCE) is low (1/5000)
• The main reasons for failure were :
– unacceptable clinical efficacy
–Historically poor PK (40%) but much
better now
34
Why compounds fail or slow down in
development
35
Drug discovery strategies
• Researchers have concentrated on maximizing
potency and selectivity (specificity) against a
biological target
but
• a good candidate requires a balance of potency,
safety and PK properties
now:
• drug metabolism and PK in drug discovery
37
process is accepted
Hierarchical in vitro screening sequences
New compound(s)
Physiochemical analysis;
measured or computed
In vitro binding against target receptor
In vitro binding against selectivity receptors
Functional activity against target receptor
In vitro intrinsic clearance
in hepatocytes
In vitro permeability
in Caco-2 cells
In vitro protein
binding
In vivo pharmacokinetic and
pharmacodynamic evaluation
41
Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80
Predictive models ADME processes
van de Waterbeemd & Gifford, Nature Reviews Drug Discovery 2, 192, 2003
42
Clearance
Renal
Hepatic
Metabolic
IR
CYP450
Polymorphism
Biliary
Others
1A2;2C9;2C19;2D6;3A4
Amino-acid
Glucuronide
Inhibition
CAR
Induction
Sulfate
AHR
PXR
43
Pharmacokinetics and
combinatorial chemistry
• PK (clearance determination) is the bottleneck
cocktail approach
and
cassette dosing
• Objectives
– 200 compounds per week for 2 scientists
44
Possible Impacts of MW
Size or molecular weight of a potential drug affects:
1. stability, ease of synthesis?
2. solubility, transport across membranes
3. bioavailability
4. Biliary excretion (interspecific differences)
5. Safety (antigenicity)
6. success in clinical trials
7. FDA approval!
48
Usefulness of PK
3-Regulatory
pharmacokinetics
52
Regulatory pharmacokinetics
• Purpose
– Necessity to understand the role of regulatory
authorities
– The role of the authorities is to ensure that marketed
drug products are safe and effective
– The authority requires basic PK information to
understand the features of the drug and factor
variation
53
Regulatory pharmacokinetics
• Guideline vs. science driven PK
– the PK guidelines were written to provide regulatory
people with the minimal information required to make a
judgment and not to provide companies with an optimal
drug development procedure
– Some companies have forgotten the true purpose of PK
studies and too often PK data appear to have been
generated with a "checklist" for regulatory authorities in
mind rather than a scientific approach to efficacy
55
In a company, is PK conducted as :
A regulatory requirement
or
For rationale drug development
56
If PK is scientifically conducted
10 critical PK and PD parameters
should be determined for each
new drug
57
Hierarchy of pharmacokinetic parameters
R&D
• Clearance
• Effective concentration range
• Extent of bioavailability
• Fraction of the available dose excreted
unchanged
• Blood / plasma concentration ratio
• Half-life
• Toxic concentration
• Extent of protein binding
• Volume of distribution
• Rate of availability
Regulatory
• Absorption
• Distribution
• Metabolism
• Elimination
Benett, 1993
58
Hierarchy of pharmacokinetic parameters
R&D
Regulatory affairs
• Independent
• Hybrid
• Have a physiological
meaning
• Only descriptive
• Clearance, distribution
• t 1/2, Cmax, Tmax
59