CLINICAL PHARMACOLOGY IN

DRUG DEVELOPMENT

70

CONCENTRATION
60
50
40
30
20
10
0
0 5 10 15 20 25 30

TIME IN HOURS

ASENT meeting, March 6, 2008

Disclaimer

Views expressed are mine and

do not necessarily reflect
official FDA Policy.
 New Molecular Entity Approvals by Fiscal Year

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

Kola I, Landis J.Can the pharmaceutical industry reduce attrition rates?

Nat.Rev.Drug.Disc. Aug 2004.
 Need/Opportunities for Innovative Methods in
Drug Development

Assess
Decrease
useful
avoidable
Biomarkers
trial failures
e.g. imaging
Evaluate Individualization
rational of
trial dosing
designs,
endpoints

Providing solutions for these issues calls

for optimal early trials and efficient use of prior knowledge
 OUTLINE

 Definitions
 Clinical Pharmacology domain
 Clinical Pharmacology studies
 Biopharmaceutics studies
 Value
 Case examples
 Conclusions
 Clinical Pharmacology is…

 Translational science in which basic

information about the relationship between
dose, exposure and response (efficacy or
safety) is applied in the context of patient care
 Major contribution of Clinical Pharmacology:
Knowledge of E-R relationship (key to
successful therapeutics) and how it is altered
by intrinsic (age, gender, renal function etc.)
and extrinsic (diet, drugs, life-style) factors of
an individual patient
 Definitions

 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

Dose Pharmacokinetics Pharmacodynamics Effect

 Absorption
 Distribution
 Metabolism
 Excretion
Concentration

MEC
Free Total
Time
 PK-PD MEASURES
Relationships Between Exposure & Response

Effect (e.g., Survival, % change in seizure

Serum Drug Concentration Emax

Peak conc. (Cmax)

frequency
AUC
EC50

PK-PD Measure
Time (e.g., AUC)
 Clinical Trials Spectrum

 Phase I, II,III and IV clinical trials

 Early and Late phase clinical trials
 Learn and Confirm trials
 Clinical Pharmacology (= Learn; phase 1
and 2) including dose response trials and
Efficacy (= Confirm; phase 3) trials
 Safety Trials: All phases
 Bioequivalence Trials
Clinical Pharmacology Domain
PK (ADME) PD

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.

Bioequivalence means the absence of a significant

difference in the rate and extent to which the active
ingredient or active moiety in pharmaceutical
equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered
at the same molar dose under similar conditions in an
appropriately designed study.
 BIOAVAILABILITY
MEASUREMENT

MONITORING PARAMETERS

 Peak Concentration: Cmax

 Time to Peak Concentration:
Tmax
 Area Under the Drug
Concentration-Time Curve:
AUC
 Single dose & Multiple dose
Bioavailability

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

Cmax and AUC

 Food effect study
High fat meal: 70
 2 eggs fried in butter

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

Current Decision Rule:

Two one-sided test procedure:
(ALSO CALLED THE 90% CONFIDENCE INTERVAL APPROACH)
• Recognizes that there will be a difference in mean values
between treatments
• Provides reasonable assurance that mean
treatment differences are acceptable

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

Pater Current Controlled Trials in Cardiovascular Medicine 2004 5:7

 GENERAL THOUGHTS/VALUES

 OCP:

The Right Dose of the Right Drug at the Right Time

for the Right Patient

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

FDA’s proactive model-based analysis

identified that the proposed dosing is sub-
optimal. Simulations suggested alternatives.
Development cycle extended.
 Regulatory Issue

 Short t1/2 drug for lowering BP

 Sustained effect desired
 Proposed dosing - QD
 Very large trial conducted
 Typically pivotal trials are not large for hypertension
 Exposure-Response analyses conducted
 Effectiveness and Safety
 Is this really a once-day-drug?
 s-Lercanidipine Steady-Stat
6.0 6.
ER Analysis
3.0 3.
0.0 X mg daily 0.
ID: 101
Clear concentration-effect 3.6 4.
relationship EC50 3.
2.4
No delay between PK and Cp
PD 1.2 1.
Nonlinear concentration- 0.0 0.
effect relationship
FDA performed the analysis 0 Time,
6 12h18 24
during NDA review

 Modeling demonstrated inadequacy of once a

day regimen
 Value Delivered by the Exposure
Response Analysis

 Supported evidence for effectiveness

 Aided in judging that QD dosing is sub-
optimal
 Provided alternatives for future development
 Prospective modeling of early PK/PD data
could have (and an EOP2A meeting)
 Avoidedlengthening drug development time
 Been more economical
 Case example 2 - Use of exposure
response for pediatric approval

FDA’s proactive model-based analysis alleviated

the need to conduct additional clinical trial for the
approval of Trileptal monotherapy in pediatrics
 Regulatory Issue

Adjunctive Monotherapy
Adults Clinical trials Clinical trials

Children Clinical trial “Model Based Bridging”

(4-16 years approach proposed by
of age) FDA

FDA/Sponsor pursued approaches to best utilize

knowledge from the positive trials to assess if
monotherapy in pediatrics can be approved without new
controlled trials
 Motivation

 Monotherapy of anticonvulsants is important

 Better safety, Ease of Rx mgmt
 Avoid unnecessary costs

 Monotherapy trials are challenging

 Reasonable ER knowledge available
 Integration of knowledge across trials and populations
is needed
 Law supports model based thinking
 Value of this type of analysis

 Modeling and simulation aided in utilizing all

previous data to justify approval without
additional controlled clinical trials
 Allowed selection of dosing guidelines in
pediatrics
 The presented approach has a greater global
impact
 Precedent was set
 Conclusions

 PK and Exposure-Response analysis can help select

suitable dose/dosing regimen and identify optimal drug
products.
 PK from early trials will help optimize the dosing
conditions for pivotal trials.
 Facilitate dosing in special populations and also provide
dose adjustment guidelines in the presence of intrinsic
(age, gender, renal function etc.) or extrinsic factors
(concomitant drugs, food etc.).
 Conclusions …. contd.

 Facilitatefindings of effectiveness as well

as help resolve safety concerns.
 E-R frame created in the approved setting
can be a powerful source for approval
consideration for additional settings (e.g.
pediatrics).
 Need/Opportunities for Innovative Methods in
Drug Development

Assess
Decrease
useful
avoidable
Biomarkers
trial failures
e.g. imaging
Evaluate Individualization
rational of
trial dosing
designs,
endpoints

Providing solutions for these issues calls

for optimal early trials and efficient use of prior knowledge
ACKNOWLEDGEMENTS

Dr. Mehul Mehta

Dr. Patrick Marroum
Dr. Robert Kumi

That’s all folks!