Ethnic differences which may affect safety/tolerability. Konstanze Diefenbach 23. AGAH-Annual Meeting (13 March 2014)

Ethnic differences which may affect safety/tolerability Konstanze Diefenbach 23. AGAH-Annual Meeting (13 March 2014)

Contents Ethnic factors Introduction into ICH-E5 Definition of ethnic factors Sensitivity to ethnic factors Case examples Moxifloxacin Warfarin Carboplatin Leflunomide Summary and Conclusion Disclaimer: The information, views, and opinions contained in this presentation are those of the author and do not necessarily reflect the views and opinions of Bayer HealthCare. 2

3 ETHNIC FACTORS

ICH-E5 To facilitate the registration of medicines among ICH regions To provide guidance on regulatory and development strategies Extrapolate foreign data to different populations Evaluate influence of ethnic factors on safety, efficacy, dose and dose regimen Minimize duplication of clinical studies Describe the use of bridging studies bridge CDP in original region? Approval in the new region Before extrapolation can be considered, the Complete Clinical Data Package, including foreign clinical data, submitted to the new region should contain: Adequate characterization of pharmacokinetics*, pharmacodynamics*, doseresponse, efficacy and safety in the population of the foreign region(s). Clinical trials establishing dose response, efficacy and safety 4

Ethnic Factors - definition ICH-E5 points out that the influence of intrinsic and extrinsic ethnic factors on the drug's efficacy and safety should be evaluated through the development process Intrinsic Ethnic Factors: genetic and physiologic characteristics Intrinsic ethnic factors are factors that help to define and identify a sub-population and may influence the ability to extrapolate clinical data between regions Extrinsic Ethnic Factors: cultural and environmental characteristics Extrinsic ethnic factors are factors associated with the environment and culture in which a person resides. Extrinsic factors tend to be less genetically and more culturally and behaviorally determined. 5

6 Ethnic Factors - definition

Sensitivity to Ethnic Factors Sensitivity to Ethnic Factors Less sensitive More Sensitive Pharmacokinetics (PK) Linear Non-linear Linear PK Non-linear PK Rate of elimination or Exposure Rate of elimination Exposure Dose Dose Dose 7

Sensitivity to Ethnic Factors Sensitivity to Ethnic Factors Less sensitive More Sensitive Pharmacokinetics (PK) Linear Non-linear Pharmacodynamics (PD) curve for both efficacy and safety Flat Steep Effect Flat PD curve Effect Steep PD curve Conc. Conc. 8

Sensitivity to Ethnic Factors Sensitivity to Ethnic Factors Less sensitive More Sensitive Pharmacokinetics (PK) Linear Non-linear Pharmacodynamics (PD) curve for both efficacy and safety Therapeutic dose range (possibly an indicator of good tolerability Flat Wide Steep Narrow 9

Sensitivity to Ethnic Factors Sensitivity to Ethnic Factors Less sensitive More Sensitive Pharmacokinetics (PK) Linear Non-linear Pharmacodynamics (PD) curve for both efficacy and safety Therapeutic dose range (possibly an indicator of good tolerability Flat Wide Steep Narrow Metabolism Minimal or multiple pathways Highly or single pathway; Metabolism by enzymes known to show genetic polymorphism Bioavailability High (less susceptibility to dietary absorption effects) Protein binding Low High Low (more susceptible to dietary absorption effects) Drug-drug, drug-diet, and drugdisease Little potential Highly likelihood interactions Mode of action Non-systemic Systemic Inappropriate use Little potential Highly likelihood Multiple co-medications Little potential Highly likelihood 10

11 CASE 1: MOXIFLOXACIN

Case 1: Moxifloxacin Ethnic difference in PK? Japan, China, Korea Tripartite co-operation 12 Research on ethnic factors: 1 st Stage: Literature-based PK comparison among populations Part of ethnic variability explained by the frequency differences in functional genetic polymorphisms of the drug metabolizing enzymes and transporters. Involvement of other factors in PK differences among populations has been suggested in some drugs: Moxifloxacin, Simvastatin and Meloxicam. 2 nd Stage: Prospective PK study

Case 1: Moxifloxacin Ethnic difference in PK? Ethnic Factors Less sensitive Moxifloxacin Pharmacokinetics (PK) Linear Pharmacokinetics are linear in the range of 50 to 1200 mg single dose Pharmacodynamics (PD) curve for both efficacy and safety Flat Meta-analysis of 4926 patients indicated that AEs were mostly mild and transient. The most frequent events were nausea (7.2%) and diarrhoea (5.7%). Therapeutic dose range (possibly an indicator of good tolerability) Metabolism Wide SD 50 to 800 mg or MD up to 600mg once daily for 10 days well tolerated in healthy volunteers (n = 103). Minimal or multiple pathways Moxifloxacin and Phase II metabolites yielded 96~98% regardless of administration, no oxidative metabolism. Bioavailability High (less susceptibility to dietary absorption effects) Absolute bioavailability about 91% and no food effect on the PK of moxifloxacin. Protein binding Low Protein binding about 45 %, mainly bound to serum albumin Drug-drug, drug-diet, and drug-disease interactions Mode of action Little potential Non-systemic No CYP related DDI Inappropriate use Little potential Little potential Multiple co-medications 13 Little potential

Case 1: Moxifloxacin Ethnic difference in PK? Bayer Data (Revised by NIHS) 0.2 Relative AUC difference 0-0.2-0.4-0.6 Chinese Caucasian Compared with Japanese 90%CI 14

Case 1: Moxifloxacin Ethnic difference in PK? Country Site PI Japan Kitasato University Tomoko Hasunuma China Peking University First Hospital Cui Yimin Korea Seoul National University In-Jun Jang 15 US SNBL Baltimore Masaru Kaneko

Case 1: Moxifloxacin Ethnic difference in PK? Moxifloxacin PK Data (AUC) Data from Bayer IMCT trial A single protocol controlling for extrinsic was employed and uniformly applied to the study populations to assess ethnic differences in PK Recommended to assess genotypes of study subjects study populations to assess ethnic differences in PK as polymorphisms of the relevant genes may affects drug PK 16

17 CASE 2: WARFARIN

Case 2: Warfarin Ethnic difference in PK and PD Influence of ethnicity on warfarin dose requirement to achieve a target INR 2-3 Warfarin label: Individualization by monitoring the PT/INR. Maintenance dose to achieve a target PT/INR is influenced by: Age Race/ethnicity Body weight Sex Concomitant medications, Comorbidities Genetic factors (CYP2C9 and VKORC1 variants) Dang et al. Ann Pharmacother 2005;39:1008-12. 18

Case 2: Warfarin Ethnic difference in PK and PD Mechanism of warfarin and its metabolism CYP2C9: CYP2C9 is the key enzyme in metabolism of the more potent S- warfarin VKORC1: VKOR is the target enzyme for warfarin to exert its anticoagulation effect VKOR is inhibited by warfarin to regenerate the reduced vitamin K from its epoxide form Tan GM, Wu E, Lam YY, Yan BP. Pharmacogenomics. 2010;11(3):439-48. Several other genes may influence variation in warfarin metabolism 19

Case 2: Warfarin Ethnic difference in PK and PD CYP2C9 variants (*2 and *3): Nonsynonymous coding variants resulting in reduced enzyme activity and decreased metabolic capacity Variants more common in Whites VKORC1 variant(s) ( 1639G>A, 1173C>T): Effects thought to be mediated through differential expression of the VKOR protein Variability in warfarin dose captured by a single polymorphism - strong linkage equilibrium between the variants Variant allels associated with a lower warfarin dose Johnson JA. Circulation 2008. 118:1383-1393 Variant allels very common in Asian 20

Case 2: Warfarin Ethnic difference in PK and PD CYP2C9 variants (*2 and *3): Nonsynonymous coding variants resulting in reduced enzyme activity and decreased FDA metabolic approvd capacity label COUMADIN (warfarin sodium) tablets contains Variants now morethe common following Whites table: VKORC1 variants: Effects thought to be mediated through differential expression of the VKOR protein (warfarin target: vitamin K epoxide reductase) Variability in warfarin dose captured by a single polymorphism - strong linkage equilibrium between variants Variant allels associated with a lower warfarin dose Variant allels very common in Asian 21

Case 2: Warfarin Ethnic difference in safety? In global trials, INR range of 2 3 established to balance benefits (reduced thromboembolic events) with risks (bleeding) for warfarin Large trials predominantly in Caucasian Data suggest it may not be the most appropriate INR range in Asians You et al. 2005: In 491 Chinese patients treated with warfarin, INR associated with the lowest hemorrhagic and thromboembolic rate was 1.8 to 2.4 Suzuki et al. 2007: In 667 Japanese treated with low-dose warfarin therapy (target INR 1.6 to 2.6) for non-valvular atrial fibrillation, rate of major bleeding/intracranial hemorrhage patients is similar to the rate observed in Western populations with fulldose anticoagulation (target INR 2 to 3) and about 2fold the rate observed in Western populations for low-intensity warfarin therapy Yu et al. 2005: In 563 Taiwanese patients with mechanical valve replacements (INR 2.5 to 3.5, risks of thromboembolism not different with an INR<2 versus >2) Asians may have greater thromboembolic protection at lower INRs than Caucasian and might be at increased risk of bleeding at lower INRs 22 Review on Ethnic difference in cardiovascuar drug response : Johnson JA. Circulation 2008. 118:1383-1393

23 CASE 3: CARBOPLATIN

Case 3: Carboplatin-induced myelosuppression Neutropenia in NSCLC studies: Combination of paclitaxel (225 mg/m 2 ) and carboplatin AUC 6 Kelly 1999 (SWOG): Grade 4 neutropenia in 35% of 188 patients Shiller 2000 (ECOG): Grade 4 neutropenia in 42% of 272 patients Ogawara 2002: Grade 4 neutropenia in 70% of 10 patients Neutropenia in epitelial ovarian cancer: Combination of paclitaxel (175 mg/m 2 ) and carboplatin AUC = 5 Takei 2003: Grade 4 neutropenia (80% in the Japanese cohort) was dose-limiting Neutropenia in NSCLC studies: Combination of docetaxel (75 mg/m 2 ) and carboplatin AUC 6 Millward 2003: Phase II study in Caucasian and Asian patients (Singapore), Grade 4 neutropenia in 70% (26% febrile neutropenia) Reduction to carboplatin AUC 4.5 at Singapore site due to high rate of febrile neutropenia: 50% febrile neutropenia at AUC 6, 40% febrile neutropenia at AUC 4.5 2/2 Asian patients at Australia site developed grade 4 neutropenia Possible explanations for susceptibility of Asians to platinum-based chemotherapies: Genetic causes, and/or differences in environmental factors, local treatment practice, and/or unique drug drug interactions 24

Case 3: Carboplatin-induced myelosuppression Ethnic diversity in drug response or toxicity, results from the combined interaction of many factors, principally differences in environment, local practice habit and regulatory control differences, drug drug interaction differences, and genetic differences 25 O'Donnell PH, Dolan ME. Clin Cancer Res 2009;15:4806-4814

26 CASE 4: LEFLUNOMIDE

Case 4: Leflunomide Leflunomide (Arava ) Immunosuppressive disease-modifying antirheumatic drug to be used in active moderate to severe rheumatoid arthritis and psoriatic arthritis Available for oral administration as tablets containing 10, 20, or 100 mg rheuma-online.de 27

Case 4: Leflunomide Ethnic difference in DILD PK comparison after a single dose of 20 mg in Japanese and Caucasian No Major Differences on PK in leflunomide administration Similar PK have been also confirmed in multiple administration 28 Taken from: Shinobu Uzu, MHLW (Japan s experience with ICH and the implementation of Guidelines)

Case 4: Leflunomide Ethnic difference in DILD Conclusion from PMDA review on leflunomide in Japan Foreign data can be extrapolated into Japanese populations in terms of doseresponse effects of leflunomide However, risks in hepatotoxicity, bone marrow suppression as well as infectious diseases were identified In terms of safety, because of small sample size in Japanese, it is difficult to conclude that safety profiles of leflunomide in Japanese are similar to foreign population. Leflunomide was approved with condition (intensive post-market surveillance) Post-marketing surveillance of leflunomide All leflunomide-administered patients must be registered into the survey before starting leflunomide therapy Serious cases of interstitial lung diseases (ILD) have been reported 5 death cases in 3 month after launch. 16 ILD cases in 3412 patients enrolled in the survey Box Warning in the label were revised to increase the precaution level about ILD 29 Taken from: Shinobu Uzu, MHLW (Japan s experience with ICH and the implementation of Guidelines)

Case 4: Leflunomide Ethnic difference in DILD Azuma A, Japan Med Associate J, 50: 405-411, 2007 30 Page 30

Case 4: Leflunomide Ethnic difference in DILD Possible explanations for differences in DILD: Potential ethnic or genetic differences between the Japanese population and the other populations: Acute exacerbations of idiopathic pulmonary fibrosis are more frequent and severe in Japanese patients (Azuma et al. 2007) Single nucleotide polymorphisms of surfactant protein D and interstitial pneumonia in Japanese population (Ishii et al. 2012) Differences in the methods used in the studies e.g. difference in the system for collecting information about AE in the post-marketing setting In Japan, active solicitation of DILD required in early phase of launch of new drugs under the Early Post-marketing Phase Vigilance (EPPV) requirement of the Japanese Health Authority, and high incidence of DILD in Japan may be because of the greater awareness about DILD (Horiuchi-Yamamoto et al. 2012) Worldwide reporting frequency basically estimated from spontaneous reports or literature reports 31

32 SUMMARY AND CONCLUSION

Summary and conclusion Some properties of a drug (e.g. chemical class, metabolic pathway, pharmacologic class) make it more or less likely to be affected by ethnic factors Characterization of a drug according to the potential impact of ethnic factors, requires: Knowledge of PK and PD properties and its inter-relationship Assessment if bridging PK and PD into clinical effectiveness and safety is adequate Careful evaluation of potential intrinsic and extrinsic factors (ethnic sensitivity report) Be prepared for the unexpected 33

Thank you for your attention Questions? 34