Exposure-Response (PK-PD) Applied to

Model-Based Drug Development:

A Case Study of Drug X

Matthew M. Riggs, Ph.D.

metrum research group LLC

2 Tunxis Rd, Suite 112 Tariffville, CT 06081

Tel: 860.670.0744 Fax: 860.760.6014

www.metrumrg.com

September 29, 2006

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 Overview
• Introduction
– PK-PD Modeling & Simulation (M&S)
a.k.a. “Pharmacometrics”
– The M&S continuum through drug development

• Example: M&S Continuum Applied to Drug X

– Phase 1  Phase 2a
– Phase 2a  Phase 2b
– Phase 2  Phase 3

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 Pharmacometrics

PROGRESSION
…the science of interpreting and describing

DISEASE
pharmacology in a quantitative fashion (e.g.
through modeling and simulation)

DOSE CONCENTRATION RESPONSE

PK PD
• Determine typical population response
• Understand and quantify variability in PK and
response

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 Drug Development = Continuum for
Model Development & Application
Preclinical Phase I Phase IIa Phase IIb Phase III

Labelling
Learn Learn Learn Confirm and post-
marketing
Efficacy MTD Efficacy Dose-response
Therapeutic efforts
Tox Human PKPD Exposure-response
Benefit
E-R Dose Adjustments
Covariate
effects
PK/PD PK/PD……..(pop)PK/PD……………………….pop PK/PD
Mechanistic
Biomarker/Surrogate………………………..Clinical endpoint

UNCERTAINTY
diminished with increased
knowledge and understanding

September 29, 2006

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 Drug X: Optimize Therapeutic Profile
using M&S Continuum
• How evident is E-R (early Phase 1)?
• Quantify therapeutic profile:
– Surrogate Markers (SM) I & II: (Phase 1)
– Dose-Response of Comparator
– Clinical Response I & SM II (Phase 2a)
– Clinical Response I & II (Phase 2b)
• Guide / support dose & formulation selection
with input into trial design
– Phase 1  Phase 2a
– Phase 2a  Phase 2b
– Phase 2  Phase 3

September 29, 2006

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Phase 1

Multiple Ascending Dose Study

• How evident is exposure-response (PK-
PD) relationship based on an early
marker in healthy subjects?

September 29, 2006

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Phase 1

Multiple Ascending Dose Study

• PK-PD relationship evident & quantifiable (nonlinear ‘Emax’ model)
• Investigated doses = concentrations within apparent efficacious
range
7 O Placebo
E * Conc
Marker  E0  max O Dose 1
6 EC50  Conc O Dose 2
O Dose 3
5 --- Model Prediction
Marker

0 1 2 3 4
Concentration
September 29, 2006
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Phase 1

PK-PD Study
• Quantify exposure-response relationship based
on expanded markers in healthy subjects, with
active comparator (Y)?
– Consider relative PK differences
– Compare PK-PD differences (e.g., Surrogate Marker I)
– Begin to define target concentrations for effects (e.g.,
Surrogate Marker II)

• Modeling Goal: Support decisions for Phase 2a

– Determine dose of X ~ comparable to comparator
dose of Y using PK and PK-PD differences
– Support selection of dose range for Phase 2a study

September 29, 2006

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Phase 1

PK-PD Study – Surrogate Marker I

• Drug X (red) was more potent than Comparator Y (blue)
• Relative potencies (EC50 of X vs. Y) very consistent across
Drug X (red),Comparator Y (blue)
multiple response variables
Median observation at each collection time for each treatment (circles)
5

PK-PD Model Prediction (solid line)

EC50 = dashed lines

( E max  R0 ) * (Conc X ) ( E max  R0 ) * (ConcY )

Response  R0  
4

EC 50 X  (Conc X ) EC 50Y  (ConcY )

Median Response

3
2
1
0

Median Concentration

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Phase 1

PK-PD Study – Surrogate Marker (SM) II

• Identified Drug X concentrations associated with SM II effect
• Consider doses that provide for target concentrations

Concentration range Concentration range

associated with “no effect” associated with “effect”
Marker II

Concentration
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Phase 1

PK-PD Study
• Drug X ‘worked’, but… what dose(s) should
go into Phase 2a?
– Obvious Choice: Dose of X ~ Comparator Y Dose
– But… what +/- multiple(s) of Dose X?

• Phase 2a: Primary endpoint = clinical

outcome measure (Response I)

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Phase 1

PK-PD Study

• Drug X ‘worked’, but what doses should go

into Phase 2a, where primary endpoint will be
a clinical outcome measure?
• Comparator Y Dose-Response for Response I
– Literature data
– Model = Nonlinear ‘Emax’ model for mean
relationship
– Uncertainty range: Based on standard errors of
parameter estimates

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Phase 1  Phase 2a

Dose-Response for Comparator Y: Response I

0

Literature data (o)

Response

Uncertainty
range:
3 based on
95% CI’s of
parameter
Mean Prediction (___) estimates
4

0 1 2 3 4
Dose Y
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Phase 1  Phase 2a

PK-PD Study

• Drug X ‘worked’, but what doses should go into

Phase 2a, where primary endpoint will be a clinical
outcome measure?
• Comparator Y Dose-Response for Response I
• Scaled for Approximate Dose-Response of Dose X
– Based on relative EC50 of Drug X vs. Comparator Y
– Accounted for PK differences
– Additional variability for uncertainty in scaling ratios

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Phase 1  Phase 2a

Scaled Dose-Response for Drug X: Response I

• Select doses to further characterize (reduce uncertainty in)
response surface
0

1
Response

4
0 1 2 3 4
Dose X

• Target doses ~ 50% (ED50), 80% (ED80) & max effects (Emax)
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Phase 2a

Phase 2a Study: Response I

• Observed results for Drug X (o) provided
the desired response range
0

1
Response

4
0 1 2 3 4
Dose X

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Phase 2a

Phase 2 M&S Plan

• Response I
– Describe exposure-response using Cmax
– Determine Cmax target to provide appropriate
response range
• Response II
– To be studied in Phase 2b
– Prolonged exposure may be required?
– Determine what doses / concentrations required for
Response II
• Consider formulation modifications to prolong
exposure, if needed, while retaining Response I
target Cmax

September 29, 2006

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Phase 2a

PK-PD for Response I

i.e. – if Target Response

Response I
Dose

Cmax (concentration)
Target Cmax Drug X

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Phase 2a

PK-PD for Surrogate Marker II

• PK-PD relationship very consistent with Phase 1 prediction
“No effect” range “Effect” range

Drug X
O Observed
(Phase 2) __

Predicted (Phase 1)
Marker II

Concentration
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Phase 2a  2b

Simulated Mean Concentration vs. Time

• With this PK profile, dose provides for Response I but may not for
6 Response II

5 From Phase 2a
Modeling
Concentration

4 To get from Phase 2b PK-PD not quantified yet =

Modeling considerable uncertainty in
target concentration range
3
Response I

Response II
1

0
0 a b c d e f g h
TIME
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Phase 2a  2b

Example: Simulated “Modified” Mean PK Time Profile

6
• Composite of PK & PK-PD Modeling to direct & support dose &
formulation choices
5
Concentration

3
Response I

2 Response II

0
0 a b c d e f g h
TIME September 29, 2006
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Phase 2  3

Monte Carlo Simulation

• Mixed effects model allows for:
– Simulation of expected PK & PK-PD variability
– Calculation of % subjects reaching each target concentration
and Response
• Optimize dose & formulation, and trial design, based on
relative balance of % of subjects to each target (may include
efficacy and safety markers) rather than just attainment of
mean
Simulated Individuals
Mean Prediction
Concentration

0 a b c d e f g h
Time
September 29, 2006
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 Summary – M&S Continuum
• M&S can, does, and should contribute to all
phases of development
• PK and PK-PD modeling have supported Drug
X clinical development
– Real time analyses
– Quantitative support for decisions based on
current knowledge & uncertainty
– Guided exploration of informative dose ranges and
narrowing appropriate candidate formulations.
• M&S to be continued as development
program of Drug X progresses

September 29, 2006

FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
23
 Questions?
metrum research group LLC

2 Tunxis Rd, Suite 112 Tariffville, CT 06081

Tel: 860.670.0744 Fax: 860.760.6014

www.metrumrg.com

September 29, 2006

FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
24