Transcript IN VITRO/IN VIVO CORRELATIONS-eval training

CLINICAL PHARMACOLOGY IN
DRUG DEVELOPMENT
CONCENTRATION
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Ramana S. Uppoor, R.Ph., Ph.D.
Division of Clinical Pharmacology-1
ASENT meeting, March 6, 2008
Office of Clinical Pharmacology, CDER, FDA
Disclaimer
Views expressed are mine and
do not necessarily reflect
official FDA Policy.
New Molecular Entity Approvals by Fiscal Year
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28 44
Number Approved
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44
34
13
11
20
25
8
17
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14
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8
2002
2003
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1993
1994
1995
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2001
Fiscal Year of Approval
Priority NME Approvals
* as of 30-Sep-2003
Standard NME Approvals
Number of NMEs Filed
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
useful
Biomarkers
Decrease
avoidable
trial failures
e.g. imaging
Evaluate
rational
trial
designs,
endpoints
Individualization
of
dosing
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
Pharmacokinetics
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Pharmacodynamics
Absorption
Distribution
Metabolism
Excretion
Concentration
Dose
MEC
Total
Free
Time
Effect
PK-PD MEASURES
Serum Drug Concentration
frequency
Peak conc. (Cmax)
Effect (e.g., Survival, % change in seizure
Relationships Between Exposure & Response
AUC
Time
Emax
EC50
PK-PD Measure
(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)
PM
PD
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
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Peak Concentration: Cmax
Time to Peak Concentration:
Tmax
Area Under the Drug
Concentration-Time Curve:
AUC
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CONCN.
CONCN.
Single dose & Multiple dose
Bioavailability
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Cmax and AUC
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Food effect study
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CONCENTRATION
High fat meal:
 2 eggs fried in butter
 2 strips of bacon
 2 slices of toast with butter
 4 ounces of hash brown
potatoes
 8 ounces of whole milk
 1000 calories, 50 % derived
from fat
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fasting
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Evaluate the food effect by
comparing the PK parameters
obtained in fed vs. fasted state
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BIOEQUIVALENCE MEASUREMENT
PHARMACOKINETIC PARAMETERS

SINGLE DOSE
AUC0-Tlast
AUC 0-Tinf
Cmax
Tmax

MULTIPLE DOSE
AUCss
Cmax
Cmin
Tmax
STATISTICAL REQUIREMENTS
FOR Bioequivalence
Current Decision Rule:
Two one-sided test procedure:
(ALSO CALLED THE 90% CONFIDENCE INTERVAL APPROACH)
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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 suboptimal. 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
 Effectiveness

analyses conducted
and Safety
Is this really a once-day-drug?
s-Lercanidipine Steady-Stat
6.0
6.
ER Analysis
3.0
Clear concentration-effect
relationship
No delay between PK and
PD
Nonlinear concentrationeffect relationship
FDA performed the analysis
during NDA review
0.0
3.6
2.4
Cp
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X mg daily
ID: 101
EC50
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0 Time,
6 12h18 24
 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 suboptimal
 Provided alternatives for future development
 Prospective modeling of early PK/PD data
could have (and an EOP2A meeting)
 Avoided
lengthening 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
Adults
Adjunctive
Clinical trials
Children
Clinical trial
(4-16 years
of age)
Monotherapy
Clinical trials
“Model Based Bridging”
approach proposed by
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
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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.
 Facilitate
findings 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
useful
Biomarkers
Decrease
avoidable
trial failures
e.g. imaging
Evaluate
rational
trial
designs,
endpoints
Individualization
of
dosing
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!