DRUG DEVELOPMENT
70
CONCENTRATION
60
50
40
30
20
10
0
0 5 10 15 20 25 30
TIME IN HOURS
50
45
28 44 44
34
40 39
40
21 37 27
35
Number Approved
31 32
30 28 30
25 8
25
13 17 22
11
20
14 13
18 19
15 17
10
10 13 13 12
9 10
5 8 8
5
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Fiscal Year of Approval
Priority NME Approvals Standard NME Approvals Number of NMEs Filed
* as of 30-Sep-2003
High attrition rate even in late
development
Assess
Decrease
useful
avoidable
Biomarkers
trial failures
e.g. imaging
Evaluate Individualization
rational of
trial dosing
designs,
endpoints
Definitions
Clinical Pharmacology domain
Clinical Pharmacology studies
Biopharmaceutics studies
Value
Case examples
Conclusions
Clinical Pharmacology is…
Clinical Pharmacology:
Pharmacokinetics (PK): What the body does to the
drug (Absorption, Distribution, Metabolism,
Excretion). For drug review purpose, PK also covers
extrinsic and intrinsic factors like drug interactions,
effect of age, gender, race, organ dysfunction, etc. PK
gives you Exposure.
Pharmacodynamics (PM): What the drug does to the
body. PD covers desirable and undesirable effects, from
biomarkers to surrogates to clinical endpoints. PD gives
you Response.
FIRST PRINCIPLES
Why Drugs Work In Vivo
Absorption
Distribution
Metabolism
Excretion
Concentration
MEC
Free Total
Time
PK-PD MEASURES
Relationships Between Exposure & Response
frequency
AUC
EC50
PK-PD Measure
Time (e.g., AUC)
Clinical Trials Spectrum
PM PG
Clinical Pharmacology &
Biopharmaceutics Studies
Pharmacokinetics/Biopharmaceutics:
Mass Balance studies with radiolabelled drug
Single and multiple dose pharmacokinetics
Absolute bioavailability
Dose proportionality
Food effects studies
Bioequivalence studies to establish the link
between the market and clinical formulations
Metabolism and drug interactions
Clinical Pharmacology &
Biopharmaceutics Studies .. contd.
Clinical Pharmacology:
Pharmacokinetics in the target population
Special population studies
Age, Gender, Race, etc.
Disease states such as renal and liver impairment
Establishment of pharmacokinetic
pharmacodynamic correlations
Bioavailability and Bioequivalence -
Definitions
Bioavailability means the rate and extent to which the
active ingredient or active moiety is absorbed from a
drug product and becomes available at the site of
action.
MONITORING PARAMETERS
70 120
60 100
50
CONCN.
80
CONCN.
40 60
30
40
20
20
10
0
0 0 5 10 15 20 25 30
0 5 10 15 20 25 30
TIME IN HOURS
TIME IN HOURS
CONCENTRATION
60
2 strips of bacon 50 fed
fasting
2 slices of toast with butter 40
4 ounces of hash brown 30
potatoes 20
8 ounces of whole milk 10
1000 calories, 50 % derived 0
from fat 0 5 10 15 20 25 30
TIME IN HOURS
Evaluate the food effect by
comparing the PK parameters
obtained in fed vs. fasted state
BIOEQUIVALENCE MEASUREMENT
PHARMACOKINETIC PARAMETERS
MULTIPLE
SINGLE DOSE DOSE
AUC0-Tlast AUCss
AUC 0-Tinf Cmax
Cmax Cmin
Tmax Tmax
STATISTICAL REQUIREMENTS
FOR Bioequivalence
General Requirement:
90% confidence intervals for AUC and Cmax have to be within
the range of: 80 – 125% (based on log transformed data)
Common CPR Encounters
Exposure-Response
OCP:
Optimal bioavailability
Dose selection
Dosing regimen selection
Dose adjustment for special populations
Dose adjustment in presence of intrinsic and extrinsic factors
GOAL: To develop good drugs/drug
products with adequate information to
improve therapeutics (with an ultimate
goal of optimal treatment for a patient)
Exposure Response Relationship
Selection of appropriate dose/regimen
Efficacy
Percentage
of
Response Toxicity
Exposure
Selection of optimal release profile
Case example 1 – Dosing regimen
Adjunctive Monotherapy
Adults Clinical trials Clinical trials
Assess
Decrease
useful
avoidable
Biomarkers
trial failures
e.g. imaging
Evaluate Individualization
rational of
trial dosing
designs,
endpoints