Case-study in Model-Based Drug Development

Dr. Sasahara
Pharsight Corporation

© Pharsight Corporation All Rights Reserved

30 May 2008, ARCS
 Reasons for inefficiencies in clinical
development …

Inefficient decision making processes (poor knowledge management)

● lack of necessary information to make informed decisions
● decisions not based on quantitative inputs
● focus on the wrong areas (e.g., speed to market as opposed to
understanding the dose response)
● loss of knowledge due to changes in staff and assignments
● inability to capture information (such as how and why decisions were made,
intellectual property, etc.)

Lack of (efficient) utilization of technology including

● Tools for computer assisted trial simulation
● Data repositories
● Standardization of tools, databases and practices
● Communicating outcomes to decision-makers

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30 May 2008, ARCS
 …. And What Can Be Done About It?

Model-Based Drug Development (MBDD)

● Rather than filling in gaps in knowledge, M&S is now being
used to better design future studies and drug development
programs:
• Optimize clinical drug development focus on
establishing exposure-response relationships to allow
correct choice of dose(s)
• Establish the use of drug-disease models and advanced
pharmacometric concepts in early drug development
• Promote the use of innovative clinical designs early in
clinical development to establish proof of concept and
exposure-response relationships

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 Model-Based Drug Development

Goal
● SMALLER NUMBER OF FAILED TRIALS
• Reduced cost associated with trials
• Increased certainty in trial designs
• Lower rate of late-stage attrition
• Studies in appropriate populations

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Differences between old and new paradigms

Historical Modelling Predictive Modelling

Approach

Available data Question

Question Get data

Model data Model data

Apply model (predict, simulate)

Conclusion Conclusion
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 Case Study
Prediction of pain relief in Japanese
patients with acute post-operative
dental pain based on studies of a
novel COX-2 inhibitor in a Western
population

Rohatagi S, Kastrissios H, Sasahara K, Truitt K, Moberly J, Wada R, Salazar D.

Pain relief model for a COX-2 inhibitor in patients with post-operative dental pain.
Br. J. Clin. Pharmacol. 2008; 66(1):60-70.

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30 May 2008, ARCS
Study Design

Randomized, double-blind, placebo- and active comparator

(celecoxib) -controlled Phase 2a study.

Patients with moderate to severe pain intensity were included

within 6 hr following dental surgery.

Pain relief was measured on a 5-point scale up to 24 hours

post-dose.

Time to onset of perceptible pain relief and time to onset of

meaningful pain relief were assessed by the patient using a
separate stopwatch for each measurement.

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30 May 2008, ARCS
Percentage of Subjects Remaining on Treatment
over Time Proportion of Subjects On Treatment
1.0
0.8
0.6

1.0
0.4

0.9
placebo
10 mg 0.8

50 mg
0.2

100 mg
0.7

200 mg
0.6
0.0

0 1 2 3 4

0 4 8 12 16 20 24

Time to Cessation, h
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Pain Model
Models included:
Pain Relief Model:
● A standard categorical response model was used to describe the
probability of pain relief (PR) over time. The PR model incorporated a
placebo effect model (fp(tij)) and a drug effect model (fD(Cij)).


exp
( β k + f p ( tij ) + f D ( Cij ) +ηi ) 
P(Yij ≥ k | ηi ) =  
 ( β k + f p ( tij ) + f D ( Cij ) +ηi ) 
 1 + exp 

• The placebo response model was described by a first order

increase in pain relief to a stable value.

• The effect of plasma drug concentration on pain relief (drug effect

model) was described using an Emax model, parameterized in
terms of a maximum possible response and drug potency.

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30 May 2008, ARCS
Pain Model (continued)
Models included:
Rescue medication model
● A hazard function (hij=h0.λ PRij) described the probability that a patient
required rescue medication, in which λ describes the decline in the
rate of rescue medication with increasing pain relief (PR)

There was a 50%

0.0 0.2 0.4 0.6 0.8 1.0

Probability of Rescue Medication
chance of requiring
rescue medication
within 20 minutes.

The rescue time

increased by 5-fold
for every unit
0 1 2 3 4
increase in PR score Pain Relief Score
1.

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Pain Model (continued)
Models included:
Models to describe the time to onset of meaningful pain relief (MPR)
● Of those subjects who did not require rescue medication, 98% achieved
MPR. This percentage was not dose-dependent.
• The logarithm of time to MPR decreased linearly with increasing dose (left panel).
● Only 46.5% of those who required rescue medication achieved meaningful
pain relief and this percentage was dose-dependent (max probability of MPR
was 72%).
• The ratio of log time to MPR to time to rescue medication declined in a dose-
dependent manner to a minimum value (inhibitory Emax-type model, right panel)

0.50 1.00
TMPR/Time of Rescue
5.0
TMPR (hr)
0.5

0.10 0.05
0.1

0 50 100 150 200 0 50 100 150 200

Dose (mg) Dose (mg)

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Do Japanese subjects need lower doses than Western
subjects?

A bridging approach allowed prediction of dimensions of pain relief

following various dosing regimens in Japanese relative to Western
populations.

Demographic variable distributions were chosen to reflect each of the two

populations:

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Predictive PK models suggest that exposure is lower after
the same dose in Japanese compared with Western
subjects.

Lower exposures as well as

reduced variability in drug
exposures were predicted for
Japanese subjects.

4000 8000 12000

AUC (ng.h/ml)
This finding is consistent with
fewer poor metabolizers and no
women in the simulated
Japanese Phase 1 study
population.
0 J W J W
100 mg QD 100 mg BID
Dosing Regimen

Kastrissios H, Rohatagi S, et al. Development of a predictive pharmacokinetic model for a novel COX-2 inhibitor.
J. Clin. Pharmacol. 2006;46(5):537-48.
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However, pain relief and time to onset of meaningful pain
relief was similar between Japanese and Western subjects

Simulated Time to Onset of Meaningful Pain Relief

Mean (SEM) Time (h)

Dose
Japanese Western
Placebo 2.46 (0.10) 2.56 (0.11)
10 mg 2.37 (0.14) 2.28 (0.13)
50 mg 2.45 (0.14) 2.40 (0.15)
100 mg 2.06 (0.15) 2.21 (0.16)
200 mg 1.90 (0.16) 1.70 (0.14)

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Illustration of Clinical Utility of Pain Relief Model

1.0
1 1
0.8 1 2
2
3
1
2
Probability

3
0.4 0.6

1
2 3
4
12 3 4
0.2

23 4
34 4
4
0.0

0 50 100 150 200

(Placebo)
Dose, mg
Y-axis is probability of pain relief score of at least 1, 2, 3 or 4 at 1.5 hours post-dose.
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Illustration of Clinical Utility of Pain Relief Model

1.0
1 1
0.8
1 2
2
3
1
2
Probability

3
0.4 0.6

1
2 3
4
12 3 4
0.2

23 4
34 4
4
0.0

0 50 100 150 200

(Placebo)
Dose, mg
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Summary of Findings
Outcomes

In comparison to placebo, the COX-2 inhibitor showed a greater

and more sustained response with the greatest degree of
improvement in pain relief occurring over the 10 – 50 mg dose
range.

Based on the results of simulations from the population PK/PD/PR

model, Japanese patients were expected to experience a similar
pain response and time to meaningful pain relief as Western
patients despite ethnic differences in demographics contributing
to differences in drug exposure.

The models developed allowed the following question to be

answered: Do Japanese subjects need lower doses than Western
subjects? Model-based Response: No.

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Concluding Remarks
Outcomes

A novel modelling approach was illustrated to show the

multidimensionality of pain relief for a COX-2 inhibitor.

The analysis permitted compilation of dose vs. response curves

for multiple endpoints to assess clinical utility and to facilitate
dose selection decisions.

Predictive exposure vs. response models were an important

component in the development of this drug, particularly in
providing a framework to bridge Caucasian data to the Japanese
population.

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30 May 2008, ARCS