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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 MBSW May 18-20, 2009 3 Background GTI Formation in a Drug Substance Prestarting Material Reagent Starting Material Intermediate By-Product Solvent Penultimate MBSW May 18-20, 2009 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 MBSW May 18-20, 2009 5 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 MBSW May 18-20, 2009 6 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 MBSW May 18-20, 2009 7 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.” MBSW May 18-20, 2009 8 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 MBSW May 18-20, 2009 9 zxy cab 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 MBSW May 18-20, 2009 10 1.5 mg/day * (1,000ng/ mg) Concentration 2 70kg Evaluation of Cancer Risk of Multiple GTIs - Derivation From TD 50 to Cancer Risk Risk 1 Risk 2 Concentration1 Concentration 2 Risk 2 = Risk 1 * Concentration 2 Concentration1 = 0.5 * Concentration 2 TD50(mg / kg / day) 1.5 mg/day * (1,000ng/ mg) Concentration 2 70kg for a 70 kg person receiving 1.5 mg/day MBSW May 18-20, 2009 11 zxy acb 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 MBSW May 18-20, 2009 12 zxy acb 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 + pA pB c + dB b + pB c = 0 = 0 Prob of developing cancer from joint CDF of A & B : pAB pAB = pA + pB MBSW May 18-20, 2009 13 zxy cab 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} MBSW May 18-20, 2009 14 zxy cab 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). MBSW May 18-20, 2009 15 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? MBSW May 18-20, 2009 16 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 MBSW May 18-20, 2009 17 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. MBSW May 18-20, 2009 18 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. MBSW May 18-20, 2009 19 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 MBSW May 18-20, 2009 20 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 MBSW May 18-20, 2009 21 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 MBSW May 18-20, 2009 22 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 MBSW May 18-20, 2009 23 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 MBSW May 18-20, 2009 24 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 MBSW May 18-20, 2009 25 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 1.0 Cancer risk of 10 -5 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 MBSW May 18-20, 2009 26 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. MBSW May 18-20, 2009 27