7-8 September 2016 Sheraton Hotel & Towers Ho Chi Minh City, Vietnam

Transcription

1 7-8 September 2016 Sheraton Hotel & Towers Ho Chi Minh City, Vietnam

2 Implementing pharmacogenomics into the clinical space to improve efficacy and safety of medication therapies Junichi Taguchi, MD Tokyo Midtown Clinic in affiliation with Johns Hopkins Medicine International Sep HMA at Ho Chi Min

3 Outline Who we are Medication related death/ Precision Medicine Understanding pharmacodynamics and Pharmacogenetics Ethnic Difference How to use in the real world

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5 Tokyo Midtown Medical Center Situated in 6 th Floor of Tokyo Midtown Tower, the heart of business, commerce, and culture in international Tokyo, encompassing offices, residences, hotels and recreational areas 5

6 Tokyo Midtown Medical Center Open in March 30, 2007 Floor area: 3, 000 squared meter Clinical areas: Outpatient Department Health Screening Centers Executive Health Center Dermatology and Plastic Surgery Department (NoAge) Outpatient Department Comprehensive Health Screening Center Executive Health Center Dermatology and Plastic Surgery Department (NoAge) Health Screening Center 6

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8 Tokyo Midtown Group Clinics Out patient clinic: Tokyo Midtown (Roppongi) 2 others in Tokyo Health Screening: Tokyo Midtown (Roppongi) Tokyo Bay Dermatology and Aesthetic : Noage (Roppongi) Dentistry : Tokyo Midtown (Roppongi) Radiology(therapy) : Tokyo Hoshasen Senior(geriatrics) : one in Tokyo, one in Kobe

9 HIMEDIC:Resort Trust VIP Membership Medical Club: Grand Himedic From members of resort hotel sharing ownership More than 8000 members joined to VIP health screening plan. First PET/CT/US-based cancer screening system in the world : from 1994, called as Yamanaka-ko Method Cancer detection: more than 3.2% at first year, about 0.24% at follow-up year Himedic Yamanaka-ko Himedic Osaka Himedic University of Tokyo 9

10 We are the fourth and the fifth Himedic MRI Tokyo Midtown Nagoya University 10 of Kyoto Tokyo Bay

11 Outline Who we are Medication related death/ Precision Medicine Understanding pharmacodynamics and Pharmacogenetics Ethnic Difference How to use in the real world

12 AERS : Adverse Events Reporting System Deaths and Serious Patient Outcomes from FDA-Approved Drugs More Than Half Million Per Year

13 How Drug Work PharmacoKinetics PharmacoDynamics (D) Effect PharmacoGenetics (G)

14 Precision Medicine "...Precision medicine -- Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type. That was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature? And that's the promise of precision medicine -- delivering the right treatments, at the right time, every time to the right person. -President Barack Obama, January 30, 2015

15 Rapid Progress of Genetic Medicine

16 Outline Who we are Medication related death/ Precision Medicine Understanding pharmacodynamics and Pharmacogenetics Ethnic Difference How to use in the real world

17 One of Pharmacogenetics Alcohol Metabolism

18 D type mutation of ALDH2, only in East Asian, Poor Metaboliser of Alcohol Dr Harada from Tsukuba U.

19 Grapefruit juice and Drug : Pharmacodynamics CYP3A4

20 CYP and Drug Metabolism

21 Metabolic phenotype/genotype PM Poor Metabolizer: little to no enzyme activity. IM Intermediate Metabolizer: decreased enzyme activity. EM Extensive Metabolizer: normal enzyme activity. UM Ultra-rapid Metabolizer: increased enzyme activity compared to extensive metabolizers.

22 CYP: Pharmacogenetics(G) and Pharmacodynamics(D) CYP PM/IM/EM (%) G or D 3A4 0/2/98 D 2D6 3/49/48 G 2C19 16/48/36 G 2C9 0/4/96 DG

23 CYP and Drug Metabolism More Genetics More Dynamics

24 Anti-platelet drugs and CYP 2C19

25 FDA warning

26 FDA recommendation

27 Good effect of PM

28 Outline Who we are Medication related death/ Precision Medicine Understanding pharmacodynamics and Pharmacogenetics Ethnic Difference How to use in the real world

29 Genetics (from Prof. Saito of NIHS Japan) Drug Metabolism CYP: CYP2A6 (*4), CYP2B6 (*4, *6), CYP2C9 (*2, *3), CYP2C19 (*2, *3, *17), CYP2D6 haplotypes (*4, *5, *10 など 13 種 ), CYP3A5 (*3) Others: UGT1A1 (*28, *6), NAT2 (*5, *6, *7), GSTM1 GSTT1 null genotypes Transporter: SLCO1B1 521T>C, ABCG2 421C>A Receptor: FCGR2A His131Arg, FCGR3A Phe158Val HLA: HLA-B*58:01, HLA-B75, HLA-A*31:01, HLA-DQA1*02:01 29

30 CYP and Drug Metabolism More Genetics More Dynamics

31 CYP2C9 南アジア (1,279) ND (331) (514) (1,979) ND (157) ND (122) ND (1,527) ND (297) *2: ND *3: (n=2,559) *2 : 430C>T, Arg144Cys (IM) *3 : 1075A>C, Ile359Leu (IM) 括弧内は解析人数 ( 文献により NT の場合有り ) Less in Asia 日中 日韓間で差なし日本と東南アジアとの差なし欧州 4 地域間で差なし (3,103) (839) (3,167) (872)

32 CYP2C19 南アジア NT (1,580) NT (895) (1,008) NT (237) (1,202) *2: *3: *17: (n=1,944) *2 : 681G>A, スフ ライシンク 異常 (PM) *3 : 636G>A, Trp212X (PM) *17: -806C>T (UM) More in Asia 括弧内は解析人数 ( 文献により NT の場合有り ) 日中 日韓間で差なし日本と東南アジアとの差なし欧州 4 地域間で差なし ND (1,625) (1,637) < (1,599) (854)

33 CYP2D6 南アジア (553) (1,031) NT (122) (1,458) >0.061 *4: *5: *10: (n=1,600) *4 : 1846G>A, スフ ライシンク 異常 (PM) *5 : gene deletion(pm) *10: 100C>T, Pro34Ser 他 (IM) 括弧内は解析人数 ( 文献により NT の場合有り ) Diversity 日中 :*10 でアレル頻度 の差日韓間で差なし 活性消失アレルは日中韓の間で顕著な差なし日本と東南アジア間で *10 の差あり欧州 4 地域間で差なし NT (1,511) (1,677) NT (1,450) (642)

34 Pharmacogenomic Biomarkers in Drug Labeling by FDA CYP PM/IM/EM (%) Warning to Poor/Intermediate Metabolizer 2D6 3/49/48 2C19 16/48/36 2C9 0/4/96 Amitriptyline, Arformoterol (2), Aripiprazole, Aripiprazole Lauroxil, Atomoxetine, Brexpiprazole, Carvedilol, Cevimeline, Citalopram (2), Clomipramine, Clozapine, Codeine, Desipramine, Dextromethorphan and Quinidine, Doxepin (1), Eliglustat, Escitalopram (1), Fesoterodine, Fluoxetine, Fluvoxamine, Galantamine, Iloperidone, Imipramine, Metoprolol, Modafinil, Nefazodone, Nortriptyline, Palonosetron, Paroxetine, Perphenazine, Pimozide, Propafenone, Propranolol Protriptyline, Quinidine, Quinine Sulfate (2), Risperidone, Tetrabenazine Thioridazine, Tolterodine, Tramadol, Trimipramine, Venlafaxine, Vortioxetine Carisoprodol, Citalopram (1), Clobazam, Clopidogrel, Dexlansoprazole, Diazepam, Doxepin (2), Drospirenone and Ethinyl Estradiol, Escitalopram (2),Esomeprazole, Lacosamide, Lansoprazole, Omeprazole, Pantoprazole, Phenytoin (2), Prasugrel (1), Rabeprazole, Ticagrelor, Voriconazole Celecoxib, Flurbiprofen, Lesinurad, Phenytoin (1), Prasugrel (2), Warfarin (1)

35 Carbamazepine Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), Hypersensitivity HLA-B*1502 in Han Chinese HLA-A 3101 in Europeans & Japanese Genetic testing for HLA-B*15:02 & HLA-A*31:01 is recommended for all CBZ-naive patients before initiation of CBZ therapy. Previously taken CBZ for > 3 months without any adverse effects, before reinitiation, genetic testing is NOT recommended (B). Previously taken CBZ for a shorter period, genetic testing should be considered (B). Patients who are positive for HLA-B*15:02 or HLA-A*31:01, alternative medications should be used as first-line therapy (A). Consideration in the choice of alternative medications should be given to the possibility of crossreactivity with structurally simiar AEDs (oxcarbazepine, lamotrigine, phenytoin, phe- nobarbital, primidone).

36 HLA-B*15:02 Japanese 0.05% 36

37 HLA-A * 31:01 南アジア (674) (400) (1,496) (170) (959) (1,790) (n=1,506) カルバマゼピンによる薬疹と関連括弧内は解析人数 ( 文献により NT の場合有り ) 日中間でアレル頻度 の差あり 日韓間で差なし 日本と東南アジア間で差あり 欧州 4 地域間で差なし (250) (8,961) (255) <0.01 (473) (187) 37

38 Allopurinol with HLA-B*5801 and of Korean descent with stage 3 or worse CKD (HLA-B*5801 allele frequency ~12%), or of Han Chinese or Thai extraction irrespective of renal function (HLA-B*5801 allele frequency ~6-8%), have been highlighted in the literature as prime examples of subjects at high risk for AHS(allopurinol hypersensitivity syndrome), marked by HLA-B*5801 hazard ratios of several hundred. Such high-risk individuals were recommended to be prescribed an alternative to allopurinol if HLA-B*5801 positive.

39 HLA-B * 58:01 南アジア (304) (449) (1,602) (170) (959) (1,790) (n=1,506) アロプリノールによる重症薬疹と関連括弧内は解析人数 ( 文献により NT の場合有り ) 日中間で アレル頻度 日韓間で の差あり 日本と東南アジア間で差あり 欧州 4 地域間で差なし (7,048) (8,862) (255) (473) (201) 39

40 Multi-ethnicity in Japan

41 Outline Who we are Medication related death/ Precision Medicine Understanding pharmacodynamics and Pharmacogenetics Ethnic Difference How to use in the real world Check HLA and CYP depending on Ethnicity Check drug combinations

42 CYP and Drug Metabolism More Genetics More Dynamics

43 Pharmacogenomic Biomarkers in Drug Labeling by FDA CYP PM/IM/EM (%) Warning to Poor/Intermediate Metabolizer 2D6 3/49/48 2C19 16/48/36 2C9 0/4/96 Amitriptyline, Arformoterol (2), Aripiprazole, Aripiprazole Lauroxil, Atomoxetine, Brexpiprazole, Carvedilol, Cevimeline, Citalopram (2), Clomipramine, Clozapine, Codeine, Desipramine, Dextromethorphan and Quinidine, Doxepin (1), Eliglustat, Escitalopram (1), Fesoterodine, Fluoxetine, Fluvoxamine, Galantamine, Iloperidone, Imipramine, Metoprolol, Modafinil, Nefazodone, Nortriptyline, Palonosetron, Paroxetine, Perphenazine, Pimozide, Propafenone, Propranolol Protriptyline, Quinidine, Quinine Sulfate (2), Risperidone, Tetrabenazine Thioridazine, Tolterodine, Tramadol, Trimipramine, Venlafaxine, Vortioxetine Carisoprodol, Citalopram (1), Clobazam, Clopidogrel, Dexlansoprazole, Diazepam, Doxepin (2), Drospirenone and Ethinyl Estradiol, Escitalopram (2),Esomeprazole, Lacosamide, Lansoprazole, Omeprazole, Pantoprazole, Phenytoin (2), Prasugrel (1), Rabeprazole, Ticagrelor, Voriconazole Celecoxib, Flurbiprofen, Lesinurad, Phenytoin (1), Prasugrel (2), Warfarin (1)

44 CYP and Drug Metabolism More Genetics More Dynamics

45 CYP3A4: Pharmacodynamics Drug combinations may change its concentration dramatically

46 CYP3A4: Pharmacodynamics AUC may increase 100 fold if combined with some medications

47 CYP3A4: Pharmacodynamics Prediction CR: the ratio of the contribution of CYP3A4 to oral clearance (CRCYP3A4) IR: inhibition ratio of CYP3A4 (IRCYP3A4) AUC will increase 1/(1 CR IR) fold Example Substrate CR Simvastatin 1.00 Inhibitor IR Voriconazole /(1-1 x 0.98) = 1/0.02 = 50 (fold)!!!

48 TOO complicated For clinical use, combination of pharmacogenetics and pharmacodynamics is important. Too many charts and FDA recommendations. So now trying to develop

49 iphone application for pharmacogenetics and pharmacodynamics

50 ありがとうございました Thank you Cám ơn anh nhiều ( カームオンアィンニウ )