1. ECOLE
NATIONALE
VETERINAIRE
T O U L O U S E
Rationale for the effective use of pharmacokinetics and pharmacodynamics in drug development
P.L. Toutain
Update: 09/10//2010

2. 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

3. PHARMACOLOGY Clinical pharmacology Pharmacokinetics Pharmacodynamics
Study of drug in a clinical context
Action of animal on drug
Pharmacodynamics
Action of drug on animal

4. Clinical trials vs. PK/PD trials

5. Dose titration PK/PD Black box Dose Response PK PD Response surrogate
Plasma
concentration

6. Dose effect vs. concentration effect relationship
External dose
EFFECT
Internal dose
DOSE
AUC = (Dose/Cl)
Less variance must be expected in the AUC/effect than in the dose/effect relationship

7. dose-effect vs. exposure- effect relationship for GnRH
LH response
Monnoyer et a.l J vet pharmaco ther 2004

8. Acute toxicity of anticancer drugs human versus mouse
Dose Ratio
External dose
AUC Ratio
Internal dose
Frequency

9. Digoxin levels in toxic and nontoxic patients
* From smith TW and haber E. J clin invest 1970;49:

10. The concentration principle in drug development: Extrapolations
From in vitro to in vivo
From experimental to target species

11. PK/PD: in vitro vs. in vivo
Response
Plasma
concentration
Body
Extrapolation
in vitro  in vivo
In vitro
Medium concentration
effet
Test system

12. PK/PD for antibiotics: extrapolation from in vitro to in vivo
Bactericidal effect
Plasma AB
concentration
Body
pathogen
In vitro
Medium AB concentration
Agar/ MH
Pathogen
MIC
Killing rate

13. The concentration principle in drug development: mechanistic approach

14. PK/PD: mechanistic approach
Response
Dose
Plasma
concentration
Response
Dose
Plasma concentration
Drug receptor interaction
Transduction
System specificity
Drug specificity, affinity &
intrinsic efficacy

15. The concentration principle in drug development
Drug action is mediated via the time course of drug concentration at the site of action
easy to demonstrate in vitro
also true in vivo

16. The concentration principle in drug development
The direct assessment of drug concentration at the actual site of action is seldom possible
but:
the drug concentration in plasma often bears a proportional relation and plasma concentrations can be used instead of site concentration

17. Indications for measuring blood levels
To determine an optimal dosage regimen
Dose
Dosage interval
Conditions of administration
Route; site etc
To guide dose adjustment

18. Dose vs. plasma concentration profile as independent variable
Clearance
Time X
Mass
(no biological information)
Concentration profile
(biological information)

19. PK vs. PD variability i.e. the 2 main sources of variability

20. PK is a critical step in understanding drug response and improving efficacy: Why ?
Many factors of variation
Interspecific
Absorption
Distribution
Metabolism
Elimination
Dose
Concentration
Factors of variation more limited
Species
Diet
Age
Gender
Diseases
Environment (husbandry,…)
EFFECTS

21. PK and PD variability well documented PK PD Effect BODY Dose Receptor
Plasma concentration
well documented
species
food
age
sex
diseases
Generally ignored
but usually more pronounced than PK variabilities (for a given species)

22. PK/PD variability for anti-inflammatory drugs
Coefficient of variation (%)
PK PD
Clearance Vss EC50 EC50
antipyretic anti-inflammatory
Nimesulide
Tolfenamic Ac
Prednisolone
T. Haake, 1997

23. Definition of the main pharmacodynamic drug properties
Efficacy
Drug action, drug effect, drug response
efficiency
Potency
Power
Sensitivity
Selectivity
Specificity

24. The 3 structural parameters of the dose-effect relationship
Emax
ED50
slope 1 1
Emax 1 1 2 2
Emax 2 2
shallow
steep
ED501
ED502
Sensitivity
Potency
Efficacy
Range of useful concentrations Selectivity

25. Efficacy vs. potency and selectivity
Efficacy, potency and selectivity
therapeutic effect
side effect A B
100
Effect 80
Concentration
A more potent than B
A = B for efficacy
B is preferable to A in a clinical context for its selectivity

26. PK/PD variabilitiy Consequence for dosage adjustment
Effect
Dose
BODY
Receptor
Plasma concentration
Clinical covariables
disease severity or duration
pathogens susceptibility
Kidney function
Liver function
...
Population approach

27. How to document variabilities
POPULATION PK/PD

28. Kinetic population vs. classical approach
Few (healthy)
laboratory
intensive
yes
narrow
Population
Many (patient)
hospital
sparse no
no (but documented)
large
Subjects
Location of study
Sampling
Subject homogeneity
Controlled variable
Inference space

29. What is the usefulness of PK
Drug discovery and development
Drug submission
Drug prescription
A requirement for regulatory affairs
A scientific tool
R & D
Drug monitoring
Guidelines
Scientific critical mass of the company
Human medicine
Very basic
Can be very sophisticated

30. Usefulness of PK
1-Drug prescription

31. 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 ?

32. Effect of adherence rate on outcome in HIV infected patients
From: Paterson DL, et al. Ann Intern Med 2000;133:21-30.

33. Usefulness of PK
2-Drug discovery

34. Drug discovery and PK Historically poor PK (40%) but much better now
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

35. Why compounds fail or slow down in development

36. Pharmacokinetics and combinatorial chemistry
Chemistry (thousands of compounds per day)
High screen throughput using molecular and cellular systems
Selection of putative active compound
Are these compounds able to become a drug
Yes, if PK properties are appropriate

37. 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 process is accepted

38. Drug discovery strategies
Hit screening
- screen large compound libraries to find molecule with a specific biological response and having a high potency
Lead generation/ optimization
- application of structure-activity relationship (SARs) to improve hits and produce leads and after optimization, to produce candidate

39. Position of in vitro and in vivo PK screen in the lead generation / optimization phases of the drug discovery process

40. Hits Leads optimized leads
Potency/selectivity screening
Hits
Leads
optimized leads
Re-synthesis
In-vitro DMPK screens
In vivo DMPK screens
Development candidate
Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80

41. Hierarchical in vitro screening sequences
Physiochemical analysis; measured or computed
New compound(s)
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
Roberts S.A. Current opinion, Drug Disc. Dev. 2003,6: 66-80

42. Predictive models ADME processes
van de Waterbeemd & Gifford, Nature Reviews Drug Discovery 2, 192, 2003

43. Clearance Renal Hepatic Metabolic Biliary IR CYP450 Others
Polymorphism
1A2;2C9;2C19;2D6;3A4
Amino-acid
Glucuronide
CAR
Inhibition
Sulfate
Induction
AHR
PXR

44. Pharmacokinetics and combinatorial chemistry
PK (clearance determination) is the bottleneck
cocktail approach
and
cassette dosing
Objectives
200 compounds per week for 2 scientists

45. PK as a scientific tool 1- Drug discovery 2- Preclinical development
drug or prodrug design
rational screening of drug and prodrug
2- Preclinical development
support for toxicology
support for pharmacodynamics
Dose titration
Interspecific prediction
New formulation
3- Clinical development

46. The drugability Some general rules to understand the differences between a pharmacologically active compound and a future marketed drugs
synthetic route, molecular weight , solubility, lipophilicity, logP, rule of five, bioavailability, efficacy, specificity, toxicity, blood brain barrier

47. Molecular weight
WDI: drugs with calculable properties

48. Possible Impacts of MW
Size or molecular weight of a potential drug affects:
stability, ease of synthesis?
solubility, transport across membranes
bioavailability
Biliary excretion (interspecific differences)
Safety (antigenicity)
success in clinical trials
FDA approval!

49. Lipophilicity and partitioning coefficient (logP & logD)
As a definition logP refers to the neutral form of the compound.

50. Lipophilicity - Hydrophilicity
Critical values for LogP
> 6 : poor water solubility
Bad dissolution
Too long residence time in lipidic phases
Drug Discovery Today, 1996, 1: 179

51. Lipophilicity - Hydrophilicity
Critical values for LogP
-3 à 0 : good hydrophilicity and paracellular passage
Slower rate of absorption than for the transcellular pathway (limited absorption area)
Influence of the MW (if too high, absorption is decreased)
< -3 : too polar and impossible to cross a membrane
Drug Discovery Today, 1996, 1: 179

52. 3-Regulatory pharmacokinetics
Usefulness of PK
3-Regulatory pharmacokinetics

53. 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

54. Regulatory pharmacokinetics
Safety
Efficacy
Clinical
trials PD PK
properties
Quality
Proofs are independent
The clinical trial is not the "pathognomonic" proof of drug efficacy and safety

55. 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

56. In a company, is PK conducted as :
A regulatory requirement or
For rationale drug development

57. If PK is scientifically conducted
10 critical PK and PD parameters should be determined for each new drug

58. 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

59. Hierarchy of pharmacokinetic parameters
R & D
Independent
Have a physiological meaning
Clearance, distribution
Regulatory affairs
Hybrid
Only descriptive
t 1/2, Cmax, Tmax