Transcript Slide 1
Linking CMC and Toxicology:
The Use of Cumulative Carcinogenic Risk
for Multiple Genotoxic Impurities Criteria
Wherly Hoffman, Daniel Ness, Elan Pharmaceuticals, Inc.
Cindy Lee, Joel Bercu, Eli Lilly and Company
Midwest Biopharmaceutical Statistics Workshop, Muncie Indiana, May 18-20, 2009
REFERENCE
Quantitative Assessment of Cumulative Carcinogenic Risk for
Multiple Genotoxic Impurities in a New Drug Substance
Regulatory Toxicology and Pharmacology
2008. 51(3):270-277.
by
Joel Bercu, Wherly Hoffman, Cindy Lee, Daniel Ness
Overview
Background
Genotoxic impurity (GTI) - formation, qualification
Evaluation of cancer risk of multiple GTIs
Derivation of cancer risks
Data source
Key factors
Simulation design
Results
Regulatory guidance on risks - one GTI, multiple GTIs
Motivation
Summary
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Background
GTI Formation in a Drug Substance
Prestarting Material
Reagent
Starting
Material
Intermediate
By-Product
Solvent
Penultimate
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Drug
Substance
4
Background
Level Relative to Drug Substance
Qualification of Genotoxic Impurities
Qualified with toxicology
studies for API (ICH Q3A)
Risk-based
approach
Not qualified
with to
toxicology qualify
studies for API
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Background-Regulatory guidance
Risk Assessment for One GTI
Available guidances
PhRMA - Muller et al. Regul Toxicol Pharmacol.
2006 Apr;44(3):198-211.
EMEA CHMP – Guideline on the limits of genotoxic
impurities. 2006
FDA draft – Genotoxic and carcinogenic impurities in
drug substances and products: Recommended
approaches. 2008
Acceptable exposure of GTI
Threshold of toxicological concern (TTC)
Adapted from food industry (Kroes et al. 2004)
TTC = 1.5 mg/day = 1 in 100,000 excess cancer risk
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Background-Regulatory guidance
Percentage of compounds not
exceeding 10-5 lifetime risk
Threshold of Toxicological Concern
TTC
TTC
World
of Carcinogens
1.5 mg/day
Dose
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Background-Regulatory guidance
Regulatory Guidance on Multiple GTIs
EMEA CHMP
Structurally dissimilar – Individual limits of 1.5 mg/day for each
impurity
Structurally similar – Total exposure to all impurities can not
exceed 1.5 mg/day
FDA (guidance similar to EMEA CHMP)
“Threshold approach to individual impurities is not intended to
limit the overall excess cancer risk to 10-5 from all impurities in a
single drug product or from multiple drug products
concomitantly administered.”
Structurally similar compounds with similar mechanisms –
“…the total daily exposure to the related compounds should be
evaluated relative to the recommended threshold exposure.”
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Background-
Motivation
FACTS
Multiple GTIs exist in a new drug substance
Risk assessment of multiple GTIs is limited currently
Acceptable level for multiple GTIs is needed
ACTION
Assess the acceptable number of genotoxic impurities
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Evaluation of Cancer Risk of Multiple GTIs - Derivation
TD50s from 2-year Carcinogenicity Studies
Compound : developing a selected tumor at a target site
DEPENDS
TD50 : average daily dose at which 50% of the population will stay tumor
free for a lifetime (Peto et al., 1984).
>1 study : TD50 (Species, Site) = harmonic mean of TD50s
>1 site and/or species : Most potent TD50 reported
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1.5 mg/day * (1,000ng/mg)
Concentration2
70kg
Evaluation of Cancer Risk of Multiple GTIs - Derivation
From TD 50 to Cancer Risk
Risk 1
Risk 2
Concentrat ion1 Concentrat ion 2
Risk 2
=
Risk1
* Concentration2
Concentration1
=
0.5
* Concentration2
TD50(mg / kg / day)
1.5 mg/day * (1,000ng/mg)
Concentration2
70kg
for a 70 kg person receiving 1.5 mg/day
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Evaluation of Cancer Risk of Multiple GTIs - Derivation
Cumulative Cancer Risk of 2 Compounds
Impurity A, dose dA,
prob of developing cancer: pA
Impurity B, dose dB,
prob of developing cancer: pB
Prob of developing cancer from joint CDF of A & B : pAB
Approximate the low rising surface of the joint CDF with a plane
y
x
z
+
+
= 0, where a, b and c are nonzero constants
b
a
c
ab > 0, ac < 0
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bac
Evaluation of Cancer Risk of Multiple GTIs - Derivation
Cumulative Cancer Risk of 2 Compounds
Impurity B, dose dB,
prob of developing cancer: pB
Impurity A, dose dA,
prob of developing cancer: pA
dA
a
+
0
b
+
pA
c
=
0
a
0
dA
a
+
dB
b
+
p A pB
c
+
dB
b
+
pB
c
=
0
= 0
Prob of developing cancer from joint CDF of A & B : pAB
pAB = pA + pB
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Evaluation of Cancer Risk of Multiple GTIs – Data source
CPD: Cancer Potency Database
Genotoxic Compounds
Carcinogenic
x%
NonCarcinogenic
(100-x) %
Gold carcinogenicity database (http://potency.berkeley.edu).
-> 756 TD50’s of carcinogenic compounds
What’s the impact of x on cumulative cancer risk?
-> Prepare CPDs
x = 10, CPD = {756 nonzoro risks and 6804 zero risks}
x = 50, CPD = {756 nonzero risks and 756 zero risks}
x = 80, CPD = {756 nonzero risks and 189 zero risks}
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Evaluation of Cancer Risk of Multiple GTIs –Key factors
Structural Alerts and Cancer Risks
Any Relationship?
underlying mechanism
conjecture
structurally similar genotoxic impurities
implication
similar cancer risks
Risk range: over 100-million fold in general
allow 100-fold for similarly structured compounds
Structural Alerts Categories: 18
(Ashby and Tennant, 1991; Cheeseman et al., 1999; Kroes et al., 2004).
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Evaluation of Cancer Risk of Multiple GTIs –Key factors
What does Similar Mean?
How do we define “similarity”?
Based on structural alert (SA)?
Based on fingerprinting?
Different techniques (Tanimoto, Manhattan, Euclidean)
How similar is similar – 30%, 60%, 80%
2D structure or 3D conformation?
Do compounds similar in structure act biologically similar?
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Evaluation of Cancer Risk of Multiple GTIs
Three key factors
Co-administration of up to three genotoxic impurities
Proportion of carcinogenic genotoxic impurities among all
genotoxic impurities: 10%, 50%, 80%
Structural similarity among multiple genotoxic impurities:
100-fold total risk range or 10-fold from one impurity
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Evaluation of Cancer Risk of Multiple GTIs
Simulation Design - General
Given a CPD with x% of carcinogenic genotoxic impurities
(x=10, 50, 80)
Estimate cumulative risk of K genotoxic impurities each at
TTC of 1.5 mg/day
1. Randomly select one cancer risk from the CPD.
2. Repeat the previous step K times.
3. Obtain cumulative cancer risk for the combination of K impurities by
summing K risks.
4. Repeat all steps 20,000 times.
Estimate 90th, 93rd and 95th percentiles from these 20,000 simulated
cumulative cancer risks.
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Evaluation of Cancer Risk of Multiple GTIs
Simulation Design – Structurally Similar
Given CPD with x% of carcinogenic genotoxic impurities
(x=10, 50, 80)
Estimate cumulative risk of K genotoxic impurities each at
TTC of 1.5 mg/day
Randomly select one risk, r, set risk range [r/10,r*10]
If r = 0, then cumulative risk = 0, else
1. Randomly select one nonzero cancer risk from [r/10,r*10]
2. Repeat Step 1 K-1 times
3. Obtain cumulative cancer risk for the combination of K impurities by
summing K risks
4. Repeat steps 1-3 20,000 times
Estimate 90th, 93rd and 95th percentiles from these 20,000 simulated
cumulative cancer risks and the 0’s.
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Evaluation of Cancer Risk of Multiple GTIs
Results – Multiple Genotoxic Impurities
The percentiles of cumulative cancer risks
No. of Impurities
Percentile of Cancer Risk
90%
93%
95%
1
3.27E-06
6.57E-06
1.03E-05
2
9.85E-06
1.50E-05
2.32E-05
3
1.73E-05
2.73E-05
3.79E-05
Note 1. Each impurity is controlled to a TTC of 1.5 mg/day
Note 2. Assume 50% of the impurities are carcinogens
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Evaluation of Cancer Risk of Multiple GTIs
Cumulative Probability (%)
Results - Multiple Genotoxic Impurities
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
10-10
90th percentile
1 impurity
2 impurities
Total N
90th%tile
Impurities Cumulative Risk
1
3.27E-06
2
9.85E-06
3
1.73E-05
3 impurities
10-9
10-8
10-7
10-6
10-5
10-4
10-3
10-2
10-1
100
Cumulative Cancer Risk
TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens
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Evaluation of Cancer Risk of Multiple GTIs
Results – Proportion of GTIs being
Carcinogenic
The 90th percentiles of cumulative cancer risks
No. of Impurities
Percent of Carcinogens
10%
50%
80%
1
1.79E-10
3.27E-06
7.71E-06
2
2.67E-07
9.85E-06
1.79E-05
3
1.09E-06
1.73E-05
3.08E-05
Note. Each impurity is controlled to a TTC of 1.5 mg/day
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Evaluation of Cancer Risk of Multiple GTIs
Results – Structural Similarity of GTIs
The %tiles of cumulative cancer risk of GTIs in 10-fold range
No. of Impurities
Percentile of Cancer Risk
90%
93%
95%
1
3.27E-06
6.57E-06
1.03E-05
2
7.70E-06
1.25E-05
1.92E-05
3
1.20E-05
1.83E-05
2.87E-05
Note 1. 50% genotoxic impurities are carcinogens
Note 2. Each impurity is controlled to a TTC of 1.5 mg/day
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Evaluation of Cancer Risk of Multiple TGIs
Cumulative Probability (%)
Results-Structural similarity with 10-fold risk
range
100
95
90
85
1 impurity
80
75
2 impurities
70
65
3 impurities
60
55
50
45
40
35
30
25
20
15
10
5
0
10-10
10-9
10-8
10-7
90th percentile
Total N
90th%tile
Impurities Cumulative Risk
1
3.27E-06
2
7.70E-06
3
1.20E-05
10-6
10-5
10-4
10-3
10-2
10-1
100
Cumulative Cancer Risk
TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens
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Evaluation of Cancer Risk of Multiple GTIs
Results – Proportion of GTIs being
Carcinogenic, with 10-fold risk range
The 90th percentiles of cumulative cancer risks
No. of Impurities
Percent of Carcinogens
10%
50%
80%
1
1.79E-10
3.27E-06
7.71E-06
2
9.83E-10
7.70E-06
1.46E-05
3
1.84E-09
1.20E-05
2.16E-05
Note. Each impurity is controlled to a TTC of 1.5 mg/day
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Evaluation of Cancer Risk of Multiple GTIs
Results – 93rd %tiles of cancer risks of GTIs
with and without 10-fold risk range
Cumulative Carcinogenic Risk in 10 -5
4.0
3.5
3.0
2.73
Risks not restricted
2.5
2.0
1.83
Risks restricted to 10-fold range
1.50
1.5
-5
1.0
Cancer risk of 10
1.25
0.657
0.5
0.0
1
2
3
Total Number of Genotoxic Impurities
TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens
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Summary
Single GTI results are consistent with literature
Favorable/lower cancer risks result from GTIs that are
structurally similar than not.
Slight increases in cancer risks result from more GTIs and
higher proportions of carcinogenic GTIs.
NOT A CONCERN!
Up to 3 GTIs, structurally related or not, are acceptable in
pharmaceutical development.
Four or more GTIs, a less likely scenario, discuss case-bycase.
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