Transcript 44_carrothers

Model Based Development of a Direct Factor Xa Inhibitor
S. Rohatagi1, T. Ozeki-Ishizuka2, Y. Nitsu2, F. Ezzet3, H. Kastrissios3, T.J. Carrothers3, S.J. Haworth1
1 – Daiichi Sankyo Pharma Development, Edison, NJ; 2 – Daiichi Sankyo, Tokyo; 3 - Pharsight Corporation, Mountain View, CA
MOTIVATION
MODEL SCHEMATIC
Modeling and simulation (M&S) were employed to make dosage
recommendations for human Phase 1 studies of CS-3030.
PROJECTED COMPARISON
Comparison across drugs shows favorable projected
response profile for CS-3030, comparable to
observed responses for comparator drugs.
Commercial
•anti-FXa activity within 0.5-0.8 IU/mL
range (Enoxaparin)
Clinical
Utility
Efficacy/
Safety
Specific objectives were to:
Phase 1/2/3 public trials
• Predict human PK-PD of CS-3030 based on animal to
human projections,
• Characterize sources of variability or safety concerns, and
• Simulate potential clinical outcomes as compared to other
anticoagulants.
1.3 anti-FXa activity correlates to 50% reduction in DVT rate
Biomarkers
Efficacy/
Safety
PT/INR of 2-3 fold (Warfarin) target PT fold increase of <1.5.
Phase I
Dose
Biomarkers
PK
Clinical
Utility
Efficacy/
Safety
•Pharmacokinetics
•Allometric scaling
of monkey PK
•Monkey exposure-response for anti-FXa activity similar to human
•Assume similar
bioavailability
•30% variability on
each PK
parameter
Non-clinical
BACKGROUND
CS-3030 is an oral, direct Factor Xa (FXa) inhibitor in development for the
management of thromboembolic diseases.
Dose
0.75
F=0.09
4 8 12
80
160
8000
6000
4000
2000
10
20
●
●
●
●
PK/PD
Disease models
Animal/human correlations
Basically integration of Knowledge
8 12
20
Time (Hr)
CL = a WT0.782 ; V= b WT
Parameter Monkey
ka
0.75 h-1
V/F
7.6 L
CL/F
0.5 L/h/kg
Projected Human
0.75 h-1
151 L
18.2 L/h
4000
Cp (ng/mL)
4
0
2000
1
0
20
10
5
1.2
1.8
2
2.2
10
15
Time (hr)
20
2.4
•
CrCL = 20 mL/min
Enoxaparin Dose
(mg/day)
10
20
40
CS3030 Dose
(mg/day)
However, doses of 10 – 80 mg show lower bioavailability and large intersubject
variability.
CS-3030 is mostly renally cleared.
50% greater F
50% lesser F
The
2000
50 kg
100 kg
0
60 yr
4
0
4
0
20
8 12
20
8 12
CONCLUSIONS AND DISCUSSION
BID
Time (Hr)
Female
80
Relationship Between Dose and
Event Probability
F=0.09
0
80
4
F=0.18
8 12
F=0.5
F=0.045
F=0.09
20
0
160
320
4
F=0.18
8 12
40
160
4
4
2
2
0
-2
10
20
-4
40
4
2
0
-2
-4
5
4
10
Arixtra, Hip, VTE
Arixtra, Knee, VTE
Arixtra, Hip/Knee, Bleeds
Warfarin (INR=2.5), Hip, VTE
Warfarin (INR=2.5), Knee, VTE
F=0.5
20
80
20
2
80
Simulated Biomarker Profiles in Humans:
Anti-Factor Xa Activity and PT
F=0.045
Integration of animal data and public literature allowed human PK-PD to be
projected under certain plausible assumptions and scenarios. Human
projections for CS-3030 identified dosing regimens which provided similar
efficacy and safety profiles to that of comparators
Lovenox, Hip, VTE
Lovenox, Knee, VTE
Lovenox, Hip/Knee, Bleeds
Warfarin (INR=2.5), Hip, VTE
Warfarin (INR=2.5), Knee, VTE
M&S was used to optimize the Phase 1 program to reduce uncertainty and test
assumptions relating to bioavailability and variability, and further to provide a
basis to:
0
0
-2
-2
-4
4
8 12
20
0
4
8 12
20
0
4
8 12
20
0
Time (Hr)
F=0.045
F=0.09
0
•Models from Monkey Data:
•Anti-FXa = 0.00782Cp – 0. 223
•PT = 1 + 0.466(anti-FXa activity)
Therefore,
• PT = 1 + 0.466( 0.00782 x Cp –0. 223 )
• Assume monkey exposure-response for antiFXa activity similar to human
4
8 12
0
20
Time (Hr)
40
4
F=0.18
8 12
F=0.5
20
80
160
2.0
1.5
2
4
6
8
10
Arixtra Dose (mg/day)
Arixtra
P(Hip VTE)=-0.63 – 0.99  dose
P(Knee VTE)=-0.78 – 0.99  dose
P(Bleed)=-0.46 + 0.42  dose
12
0
20
40
60
80
Lovenox Dose (mg/day)
Lovenox
P(HipVTE)=-0.63 – 0.028  dose
P(KneeVTE)=-0.78 – 0.028  dose
P(Bleed VTE)=-0.46 + 0.013  dose
1.0
0.5
5
10
0.0
20
2.0
1.5
1.0
0.5
0.0
0
4
8 12
20
0
Time (Hr)
4
8 12
Relative potency of CS-3030 is 3 times that of
enoxaparin sodium (Lovenox®) for anti-FXa
activity, suggesting doses up to 40 mg/day may
provide similar efficacy and safety profiles to that
of enoxaparin for doses up to 100 mg/day.
100
Projected Profile
100
0
100
-4
Comparison of clinical events was made using publicly available literature for
three comparators: warfarin, enoxaparin sodium (Lovenox®) and fondaparinux
sodium (Arixtra®).
60
Base=1.5
It was assumed that PK-PD relationships observed in cynomolgus monkeys apply
to humans.
Influences of patient demographics and laboratory values were investigated on
response to CS-3030.
1.6
Assumes F = 0.09
2) 2- to 3-fold increase in PT (based on warfarin)
Ranges of doses and bioavailability fractions were intended to compensate for
any misspecification due to projection method or underlying assumptions.
1.4
4000
1) anti-FXa activity within 0.5-0.8 IU/mL range (based on enoxaparin)
PK/PD for a range of CS-3030 doses (10 to 320 mg), regimens (single dose, once
daily (QD) and twice daily (BID)), and bioavailability fractions (4.5 to 50%) were
simulated.
5
Steady State 80 mg: Average PT
Hip VTE
Knee VTE
Major Bleeds
20
40
60
80
Major Bleeds (%)
What types of models
0
0
As early as possible
20
80
●
8 12
DVT (%)
40
60
When do we start?
4
40
Human projections from animal FXa activity suggest doses up to 40 mg/day CS-3030 may
provide similar efficacy (prevention of deep vein thrombosis) and safety (risk of bleeding)
profiles to that of enoxaparin following hip and knees surgeries.
20
●
160
Base=0.19
0
10
For a subject with severe renal impairment, average anti-FXa activity was approximately
double that a healthy subject. This may suggest that appropriate dose adjustment may be
warranted if target anti-FXa activity were to be maintained close to target values.
0
●
●
●
Think prospectively
Provide the context for evaluating New Chemical Entities (NCEs)
Inform key multi-faceted development decisions
◦
Product profiles vs. key competitors
◦
Treatment opportunities (mono vs. combo, doses)
◦
Special populations and covariates
Communicate uncertainty in these attributes to decision makers
Support informed Go/No-Go decision-making
Ideally, critical development decisions should leverage relevant public and
proprietary data
Make model the basis of developing drugs
Female
0
●
●
●
50 kg
100 kg
F=0.5
80
40
50 mg
100 mg
200 mg
400 mg
50% greater F
20
8 12
4
0
Renal impairment was expected to influence drug exposure, and therefore PD.
effect was smaller for PT response than anti-FXa activity.
HEM, CS-3030 QD, Steady-State
0.7
50 100
0
log(anti-FXa)
What should we do?
0.6
CrCL = 20 mL/min
F=0.18
F=0.09
F=0.045
2000
Models were developed for anti-FXa activity and fold-increase (i.e., multiples of
the baseline value) in PT using the following criteria to determine the target dose
range:
0.5
BID
4000
Predicted human pharmacokinetics (PK), biomarker responses (PD), and clinical
outcomes were obtained using appropriate projection methods and PK/PD data
from cynomolgus monkey, relative potency data and literature data.
0.4
60 yr
log(PT)
We model the drug as part of analysis.
We are reactive
0.3
6000
log(anti-FXa)
●
●
0.2
50% lesser F
8000
Allometric scaling was used to predict human pharmacokinetics.
What do we do now?
0.1
0
40
0
From: Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical
Products, FDA, March 2004. Page 24.
0
Simulated PK profiles for
10, 20, 40, 80, 160 and
320 mg QD (left) and BID
(below) at steady-state
320
8
If a single criterion was used, e.g. anti-FXa activity only, then a dose of 40 mg provided
50% time within the targetted range.
Steady State 20 mg: Average Anti-Xa (IU/mL)
F=0.5
Event Probability (%)
20
40
60
METHODS
F=0.18
20
5000
0
Simulated PK and Biomarker Profiles:
Special Populations
Conc (ng/mL)
500
F=0.045
6
Proportions of the anti-FXa and PT profiles within the targeted range were consistently
larger for BID regimens as compared to QD regimens.
0
concept to drug development has the potential to significantly improve it. FDA scientists
use, and are collaborating with others in the refinement of, quantitative clinical trial
modeling using simulation software to improve trial design and to predict outcomes. It is likely
that more powerful approaches can be built by completing, and then building on, specific
predictive modules.”
Simulated PK Profiles in Humans:
Allometric Scaling from Monkey Data
Prothrombin time (PT) prolongation is known to be mediated by FXa inhibition;
therefore, determination of PT and anti-FXa activity during preclinical
development provides a basis for driving the drug development process towards
selection of doses associated with target anti-FXa activity and PT/INR range.
Event Probability (%)
20
40
60
Model-based drug development involves building mathematical and statistical characterizations
of the time course of the disease and drug using available clinical data to design and validate the
model. The relationship between drug dose, plasma concentration, biophase concentration
(pharmacokinetics), and drug effect or side-effects (pharmacodynamics) is characterized,
and relevant patient covariates are included in the model. Systematic application of this
3
None of the doses met the dual criteria of anti-FXa activity and PT response. Rather,
target levels were achieved only partially over the dosing interval.
RESULTS – PK/PD MODELING
An International Normalized Ratio (INR) of 2-3 fold is generally considered a safe
and effective anticoagulant range, thereby serving as a practical guide to dose
selection for clinical use.
2.5
SUMMARY OF RESULTS
Biomarkers
In animal studies, CS-3030 is cleared largely by the kidney. It is not metabolized
by CYP 450 isozymes and therefore is expected to have low potential for drugdrug interactions.
Cp (ng/mL)
“Opportunity: The concept of model-based drug development, in which pharmaco-statistical
models of drug efficacy and safety are developed from preclinical and available clinical data,
offers an important approach to improving drug development knowledge management and
development decision making.
1.5
Fondaparinux Dose
(mg/day)
PK
Model Based Drug Development – a
FDA Critical Path Initiative
QD regimen, VTE, Hip
BID regimen, VTE, Hip
QD regimen, Bleed, Hip
BID regimen, Bleed, Hip
Warfarin (INR=2.5), VTE, Hip
Warfarin (INR=2.5), Bleed, Hip
70
= Lovenox, Arixtra and others
= CS-3030
0
Modeling and simulation (M&S) was employed to recommend doses for human Phase I studies of a direct
Factor Xa (FXa) inhibitor, CS-3030. Predicted human pharmacokinetics (PK), biomarker responses (PD), and
clinical outcomes were obtained using appropriate projection methods and PK/PD data from cynomolgus
monkey, together with literature data. Models were developed for anti-FXa activity and fold-increase in
prothrombin time (PT) compared to baseline using the following criteria to determine the target dose
range: (1) anti-FXa activity within 0.5-0.8 IU/mL range (based on enoxaparin) and (2) 2- to 3-fold increase
in PT (based on warfarin). PK/PD for a range of CS-3030 doses (10 to 320 mg), regimens (single dose, once
daily (QD) and twice daily (BID)) and bioavailability fractions (4.5 to 50%) were simulated. The ranges of
doses and bioavailability fractions were intended to compensate for any misspecification due to projection
method or underlying assumptions. Influences of patient demographics and laboratory values were
investigated on response to CS-3030. No one dose met the dual criteria of anti-FXa activity and PT
response. Rather, target levels were achieved only partially over the dosing interval. If a single criterion
was used, e.g. anti-FXa activity only, then a dose of 40 mg provided 50% time within the targeted range.
Renal impairment was expected to influence drug exposure, and the effect was smaller for PT response
than anti-FXa activity. Appropriate dose adjustment is thus possible for different populations. Human
projections from animal FXa activity suggest doses up to 40 mg/day CS-3030 may provide similar efficacy
(prevention of deep vein thrombosis) and safety (risk of bleeding) profiles to that of enoxaparin doses up to
100 mg/day following hip and knees surgeries. In conclusion, M&S led to identification of key elements to
be studied earlier than usual, i.e., bioavailability and the effect of renal clearance, and the FIM study
could be designed accordingly. This illustrated the application of M&S to guide drug development and
inform the design of clinical trials.
OBJECTIVES
Event Probability (%)
10 20 30 40 50 60
ABSTRACT
20
0
10
20
30
CS-3030 Dose (mg)
40
●Estimate the likely quality of Phase 2 dose-response in Phase 1
planning.
●Quantify the effect of covariates, the magnitude and sources of
uncertainty, and key assumptions.
This example illustrates the application of M&S to guide drug development and
inform the design of clinical trials.