Ethnic Differences in PK and PD of Anti-Rheumatic Drugs

Transcription

1 2010 China-Japan Symposium on Global Clinical Trials and Ethnic Factors May 28 th, 2010, JW Marriott Hotel Beijing Ethnic Differences in PK and PD of Anti-Rheumatic Drugs Shinichi Kawai, MD, PhD Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine

2 S. Kawai

3 (Kawai S. J Orthop Sci. 2003;8:259)

4 Immunosuppressive Drugs

5 Immunosuppressive Drugs for RA Anti-Metabolites Methotrexate, Azathioprine Calcineurin Inhibitors Cyclosporine, Tacrolimus T Cell T Cell APC Proliferation Function Pro-inflammatory Cytokines Inflammation & Immune Responses S. Kawai

6 H2N N OH N N N CH2 H N Folic acid CO H N COOH CH CH2 CH2 COOH H2N N NH2 N CH3 N CH2 N CO N Methotrexate H N COOH CH CH2 CH2 COOH

7 S. Kawai 1 st Visit 1 Year After

8 Interstitial Pneumonitis Complicated with MTX Therapy in RA Patient

9 (Modified from Kawai S. Nikkei Medical, Oct 2008)

10 RA 329 (F 265) MTX 144 (43.8%) >8mg/w 37 (24.7%) n MTX Doses (mg/w)

11 Relationship between Ages and MTX Doses of RA Patients in Our Clinic MTX Dose (mg/w) Age

12 Calcineurin Inhibitors

13 Tacrolimus and Cyclosporine Molecular formula C 44 H 69 NO 12 H 2 O C 62 H 111 N 11 O Macrolide 12 Molecular weigh Cyclic Polypeptide (Kitahara K & Kawai S. Curr Opin Rheumatol. 2007;19:238)

14 Mechanism of Action of Tacrolimus in T Cell T Cell PLC CD3 IP3 Ca Ag TCR IP3 Ca CD4 PLC Tacrolimus CaM CaM DAG P P CaN CaN FKBP DAG Activation of PKC NFAT Jun AP-1 NFAT CaN Fos AP-1 Jun Fos Activation of PKC Production of Cytokines

15 Human Tacrolimus-Binding Proteins FKBP a Refseq ID Locuslink b Class Chromosome FKBP12 FKBP C 20p13 FKBP12.6 FKBP1B 2281 C 2p23 FKBP25 FKBP N 14q21 FKBP135 KIAA N 9q32 FKBP36 FKBP TPR 7q11 FKBP37 AIP 9049 TPR 11q13 FKBP38 FKBP TPR 19p12 FKBP51 FKBP TPR 6p21 FKBP52 FKBP TPR 12p13 FKBP13 FKBP ER 11q13 FKBP19 FKBP ER 12q13 FKBP22 FKBP ER 7p15 FKBP23 FKBP ER 2q31 FKBP60 FKBP ER 7p11 FKBP65 FKBP ER 17q21 C = cytoplasmic, N = nuclear, TPR = TPR-containing, ER = secretory pathway. a FKBPs are grouped by subfamily (see Results section). b Locuslink IDs and chromosomal positions as recorded in the NCBI Locuslink database are shown. (Rulten SL, et al. Mamm Genome 2006;17:322)

16 Cyclophilins kda Distribution CypA 18 cytoplasm CypB 22 secretory pathways CypC 23 secretory pathways CypD 22 mitochondria CypE ND nuclear Cyp40 40 cytoplasm CypNK ND cytoplasm ND; not determined (Kitahara K & Kawai S. Curr Opin Rheumatol 2007;19:238)

17 Cyclosporine

18 Year Author Study design Period Dose No. of patients Results Ref Hetland et al. R, DB, PC 52wk (1) MTX 7.5mg/wk + CyA 2.5mg/kg/day + i.a. Betamethasone 160 CyA+MTX > MTX 50 (2) MTX 7.5mg/wk + i.a. Betamethasone 2006 Karanikolas et al. O, R, P 12mo (1) CyA 2.5-5mg/kg/day (2) LEF 20mg/day (3) (1) + (2) 106 CyA+LEF > CyA or LEF Sarzi-Puttini et al. O, R 12mo (1) CyA 3-5mg/kg/day + MTX mg/wk (2) CyA 3-5mg/kg/day + HCQ 400mg/day (3) CyA 3-5mg/kg/day 105 CyA+MTX > CyA+HCQ Miranda et al. R, DB, PC 12mo (1) CyA 2.5-5mg/kg/day + Clq 150mg/day (2) CyA 2.5-5mg/kg/day 149 NS Gerards et al. R, DB, PC 48wk (1) CyA 2.5-5mg/kg/day + MTX mg/wk (2) CyA 2.5-5mg/kg/day 120 CyA+MTX > CyA Marchesoni et al. R, SB 12mo (1) CyA 3-4mg/kg/day + MTX 10-20mg/wk (2) MTX 10-20mg/wk 61 CyA+MTX > MTX van den Borne et al. R, DB, PC 24wk (1) Clq mg/day (2) Clq mg/day + CyA 1.25mg/kg/day (3) Clq mg/day + CyA2.5mg/kg/day 88 CyA+Clq > Clq Bendix et al. R, DB, PC 6mo (1) CyA2.5-5mg/kg/day + i.m. gold 20-40mg (2) i.m. gold 20-40mg 40 NS Tugwell et al. R, DB, PC 6mo (1) CyA 2.5-5mg/day + MTX maximal tolerated dose (2) MTX maximal tolerated dose 148 CyA + MTX > MTX 42 O; open trial, R; randomized, DB; double blind, SB; single blind, PC; placebocontrolled Clq ; chloroquine, CyA; cyclosporin A, HCQ; hydroxychloroquine, mpsl; methylprednisolone, MTX; methotrexate, SSZ; sulfasalazine NS; not significant (Kitahara K & Kawai S. Curr Opin Rheumatol 2007;19:238)

19 Tacrolimus

20 ACR20 & 50 Response Rates for Tacrolimus Therapy in American RA Patients % Patients Placebo 1 mg 3 mg 5 mg (Furst DE, et al. Arthritis Rheum 2002;46:2020)

21 ACR20, 50, 70 Response Rates for Tacrolimus Therapy in American RA Patients (Yocum DE, et al. Arthritis Rheum 2003;48:3328)

22 ACR20 & 50 Response Rates for Tacrolimus Therapy in Japanese RA Patients (4Mo) (%) 50 *** Placebo 1.5mg 3 mg ACR20 ACR50 (Kondo Y, et al. J Rheumatol 2004;31:243) *** p<0.001 (vs. placebo) # p<0.05 (vs.1.5mg/day)

23 Effects of Tacrolimus on RA Patients CRP mg/dl pre 4W 8W 12W 16W 1 ESR mm/hr pre 4W 8W 12W 16W Placebo 5 Placebo ** P<0.01 * *** *** 3mg/day 1.5mg/day ** *** P<0.001 *** 3mg/day * P<0.05 * 1.5mg/day *** *** (Kondo Y, et al. J Rheumatol 2004;31:243)

24 56y.o. Female Patient with RA 5mg/d Prednisolone 4mg/d 3mg/d MTX 10.5mg/w Tacrolimus 3mg/d 2mg/d Hb g/dl Folinate 40mg, 5d Admission Anemia ESR mm/h ESR Serum CRP mg/dl Serum CRP Kawai S & Akimoto K

25 ACR20, 50, and DAS28 Response Rates for Tacrolimus and Mizoribine in Japanese RA Patients (Kawai S, et al. J Rheumatol 2006;33:2153)

26 Open Study of Tacrolimus in the Elderly Japanese RA Patients 100 ACR20 ACR50 80 ( ): Patients Response Rate (%) % (27) 18.5% (10) 40.0% (10) 58.6% (17) 0 All (n=54) Insufficient to MTX (n=25) Insufficient to DMARD (n=29) [Kawai S & Yamamoto K. Rheumatology (Oxford) 2006;45:441]

27 Comparison of ACR Response Rates to Tacrolimus in RCT for RA Patients * * * * * * Not determined (Kitahara K & Kawai S. Curr Opin Rheumatol 2007;19:238)

28 % 34.4 % of Patients % 40% Stop Placebo 1 mg 3 mg 5 mg (Furst DE, et al. Arthritis Rheum 2002;46:2020)

29 Increase in Serum Cr after Tacrolimus & MTX Therapy in American RA Patients (Kremer JM, et al. Arthritis Rheum 2003;48:2763)

30 Cumulative Treatment Cotinuation Rate to Tacrolimus Therapy for RA Patients 100 Cumulative treatment continuation rate (%) Gastroenteropathies Other Reasons Adverse Reactions Total (n=42) Infections, Hyperglycemia, Hypertension, Renal Dysfunction, etc Administration period (days) (Akimoto K, et al. Clin Rheumatol, 2008;27:1393

31 Biological Agents

32 Recent Biological Agents Rituximab a-cd20mab Ocrelizumab a-cd20mab Abatacept (CTLA4-Ig) Proinflammatory Cytokines TNF, IL-1, IL-6 Neutrophils S. Kawai Infliximab Etanercept Adalimumab Tocilizumab Macrophages

33 TNF Adalimumab Etanercept Infliximab

34 Various Biologic Drugs: TNF Antagonists Compound Approved Chimeric anti-tnf mab (lgg1) TNF-receptor p75 lgg1 construct Fully human anti-tnf mab (IgG1) In late-stage development PEGylated humanized anti-tnf Fab fragment TNF-receptor p55 PEG Infliximab Etanercept Adalimumab CDP870 PEG-sTNF-R1 Human Mouse Synthetic element = Polyethylene glycol

35 Infliximab

36 Concentration versus Time Curves for Infliximab in Our RA Patients (Nishio S, et al. Mod Rheumatol 2009;19:329)

37 PK Data for Our RA Patients and A Japanese Clinical Trial C1h (µg/ml) Ctrough (µg/ml) t 1/2 (hrs) Patient 1 (1.5 mg/kg) Patient 2 (1 mg/kg) Trial median* (Interquartile range) ( ) (< ) ( ) (Nishio S, et al. Mod Rheumatol 2009;19:329)

38 Fcg Receptor Gene Polymorphisms in Our RA Patients Controlled by Low-Dose Infliximab Patient 1 Patient 2 FcγRIIA 131H/H 131H/H FcγRIIIA 176F/F 176F/F FcγRIIIB NA1/NA2 NA2/NA2 (Nishio S, et al. Mod Rheumatol 2009;19:329)

39 5 Cumulative Incidence Rate (%) Male Aged Advanced RA Pulmonary Diseases Bacterial Pneumonia Interstitial Pneumonia Pneumocyctis pneumonia Tuberculosis Days since Start of Administration of Infliximab (Takeuchi T, et al. Ann Rheum Dis 2008;67:189)

40 Comparisons between PMS of Infliximab and Etanercept in Japanese RA Patients Infliximab Etanercept Duration Patient Number 5,000 7,091 Adverse Event 1,401 (28.0%) 2,173 (30.6%) Severe A.E. 308 (6.2%) 403 (5.7%) Pneumonia 108 (2.2%) 102 (1.4%) Tuberculosis 14 (0.28%) 10 (0.14%) PCP 25 (0.50%) 16 (0.23%) Int. Pneumonia 22 (0.44%) 44 (0.62%) PCP= Pneumocystis Pneumonia (Takeuchi T, et al. Ann Rheum Dis 2008;67:189) (Koike T, et al. J Rheumatol. 2009;36:898)

41 (Risk Factors: Elderly; >6mg Prednisolone; Pulmonary Diseases) 100 Cumulative Probability of Pneumocystis Pneumonia (%) With 3 risk factors (n=7) With 2 risk factors (n=13) With 1 risk factors (n=49) With 0 risk factors (n=54) Weeks (Harigai M, et al. N Engl J Med 2007; 357:1874)

42 Etanercept

43 Structure of Etanercept

44 Serum Etanercept in Japanese Volunteers (Kawai S, et al. J Clin Pharmacol 2006;46:418)

45 Comparison of PK of Etanercept between Japanese & American Volunteers (Kawai S, et al. J Clin Pharmacol 2006;46:418)

46 Relationship between AUC 0- and Dose of Etanercept in Japanese & American Healthy Subjects 500 AUCinf (mg hr/l) y = x R 2 = US ( & ) JP (0881A1) DOSE (mg) (Calculated from Kawai S, et al. J Clin Pharmacol 2006;46:418)

47 Simulation of Serum Etanercept Concentration Serum Concentration Concentration of Etanercept (ng/ml) mg sc t max 47 h C max ng/ml t 1/2 80 h Time Time (week) (weeks) (Calculated from Kawai S, et al. J Clin Pharmacol 2006;46:418)

48 Comparison of PD of Etanercept between Japanese & American Patients Improvement / /50 32/ /79 Placebo ETA 10mg 2 times/w ETA 25mg 2 times/w / /77 0 p vs Placebo Fisher p 0.01 vs Placebo χ 2 test) p vs Placebo χ 2 test)