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1 미니픽을활용한비임상시험기법및활용 안전성평가연구소동물모델연구그룹황정호

2 안전성평가연구소소개

3 1. 안전성평가연구소

4 2. 역할과책임

환경생물연구그룹 생태독성연구그룹 환경화학연구그룹 생명자원연구그룹 경남QA팀 분자독성연구그룹 바이오시스템연구그룹 독성정보연구그룹 세포모델연구그룹 생체모사연구그룹 생활안전독성연구부

5 3. 조직및인력현황 호흡기질환제품유효성평가연구단 차세대의약평가연구단 소장 감사실 산업지원팀 기술협력실 글로벌협력팀 부소장 화학물질위해성평가위원회 화학물질위기대응 TF 팀 전북분소 경남분소 예측독성연구본부 첨단독성연구본부 연구전략본부 경영본부 전북병리연구그룹 전북분석연구그룹 전북일반독성연구그룹 흡입독성연구그룹 동물모델연구그룹 전북QA팀 환경거동노출연구그룹 환경생물연구그룹 생태독성연구그룹 환경화학연구그룹 생명자원연구그룹 경남QA팀 분자독성연구그룹 바이오시스템연구그룹 독성정보연구그룹 세포모델연구그룹 생체모사연구그룹 생활안전독성연구부 융합독성연구부 대전 QA팀 운영지원팀 연구정책팀 연구조정팀 중소기업협력센터 문화홍보팀 기획예산팀 인재개발팀 정보전산팀 총무회계팀 구매자재팀 안전시설팀 전북행정지원실 경남행정지원팀

6 4. 분소현황

7 5. 주요연구분야

8 5. 주요연구분야

9 5. 주요연구분야

10 6. 동물모델연구그룹주요연구분야 화학물질, 의약품안전성평가를통한난치성질환극복과 국민의건강한삶을견인 기간 : 20 ~ 기간 : 14 ~ 기간 : 14 ~ 기간 : 18 ~ 19(1 년 ) 예산 : 30,000 백만원 ( 지역 ) 예산 : 공동연구 (GIST) 예산 : 공동연구 (KAIST) 예산 : 50 백만원 기간 : 18 ~ 21 기간 : 18 ~ 20 기간 : 18 ~ 20(3 년 ) 기간 : 17 ~ 18(1 년 ) 예산 : 600 백만원 ( 연구재단 ) 예산 : 900 백만원 ( 산자부 ) 예산 : 600 백만원 예산 : 200 백만원 ( 산자부 )

11 6. 연구소의미션 표준화 공공성 정책 규제독성자료생산및안전성평가가이드라인제시 국가긴급현안해결및사회문제해결형사업국민안심, 안전한사회 독성연구결과를통한화학물질규제, 의약품허가관리등

12 미니픽을활용한비임상시험 12

13 실험동물

14 실험동물 실험동물로서의개 1. 온순한성격 2. 사육번식의용이성 3. 약물의투여, 채혈, 채뇨등의처치가비교적쉬움 4. 유전적고정 5. 혈액, 혈청생화학, 장기중량, 조직형태의정보등의적은편차 6. 풍부한배경자료 Dog 의문제점 : 1. Dog 의감수성 : 극단적으로낮은용량에서강한부작용이관찰되는사례 ( 암, 관절염치료제 ) 2. 섬세한부작용정보파악이불충분함. 3. 구토가심함 ( 글리벡의부작용 )

15 실험동물 실험동물로서의원숭이 1. 사람과의유사성 ( 바이오의약품 )-외삽이바로가능함. 2. 면역학적연구, 유전공학, 뇌연구및단백질공학등에유용한결과를제공함 Monkey 의문제점 : 1. 동물자원확보 2. 인수공통전염병 3. Handling 4. 전문가의필요성 5. 낮은수태율과산자수 6. 높은지능으로풍부한 복지가필요함.

16 실험동물로서의미니픽 Cross-species infection Anatomic and physiologic similarities Organ size Period of pregnancy Litter size Transgenic technique Legally approved 1. 종특이적인이해의부족 2. 데이터해석과경험이적음 3. 배경자료의부족 4. 개, 원숭이사용의표준화 ( 비설치류시험 ) 1. 피부평가 ( 피부투과성, 대사등 ) 2. 소화관흡수에대한평가 3. 독성의종특이성여부규명

17 미니픽의종류 40kg 이하비임상시험사용 ( 안전성평가, 유효성평가등 ) Q. 왜미니픽인가? 피부형태와기능 소화기형태와기능 장기크기와구조 Gottingen Micro Yucatan Micropig Vietnam potbellied 다산 무균화가능 유전자조작 40-80kg 의생명과학, 재생의학사용 ( 바이오장기, 인체대체재 ) Chicago Yucatan Hanford Sinclair(Hormel) NIH

18 포유동물의계통도

19 미니픽의역사와계통

20 미니픽의분포

21 미니픽의시야

미니픽의특징 생리학적특징 Item Detail Life span 10-15 yrs Food intake 20~25

Respiration rate 20 ± 10 Body temp 38 ± 1 청력 성품 Shy Curious Social

22 미니픽의특징 생리학적특징 Item Detail Life span yrs Food intake 20~25 g/kg/day Water intake 80~120 ml/kg/day Heart rate 80 ± 15 Respiration rate 20 ± 10 Body temp 38 ± 1 청력 성품 Shy Curious Social Clever Greedy 습성 Three areas Sleeping Eating Defecation Social contact Biting/chewing

미니픽동물실험 Pigs are not predators they are prey Do establish trust 교감 1) Slow motions gentle voice 2) Hand feeding Treats 3) Squat to be less imposing Pigs are sensitive to stress A

intelligent and trainable Prepare the pig for the treatment 둔감, 훈련 1) Routines can easily be learned 2) Training based on positive reinforcement (clic ker training) can be applied

23 미니픽동물실험 Pigs are not predators they are prey Do establish trust 교감 1) Slow motions gentle voice 2) Hand feeding Treats 3) Squat to be less imposing Pigs are sensitive to stress A stress free environment provides a positive experience for technician and animal 안정 1) Quiet working place without sudden noise and events 2) Let the pig know where you are Pigs are intelligent and trainable Prepare the pig for the treatment 둔감, 훈련 1) Routines can easily be learned 2) Training based on positive reinforcement (clic ker training) can be applied successfully The Minipig tries to co pe with a new situation Every contact triggers a learning process We are training the animal whether we are aware of it or not We can influence that process

24 미니픽 Handling Talk quietly ( 조용히 ) Move slowly ( 천천히 ) Handle often ( 자주 )

25 Non-clinical study; Minipig as Non-rodent species

26 Regulatory Toxicology 26

27 Species selection as non-rodent

28 General Techniques for Minipig

29 미니픽의보정

30 경구투여 (Per Oral; PO)

31 경구투여 (Per Oral; PO) 31

32 경피시험 (Dermal) Dosage area = 체표면의 10% 체표면 (m 2 )= 70/1000 x 체중 (kg) x 0.75 <Shaving and marking the area>

33 경피시험 (Dermal) 33

34 근육내투여 (Intra Muscular;IM) Dosage: General dose: 0.25 ml/kg Maximum dose: 0.5 ml/kg <Cervical muscle behind the ear, hind leg can be used>

35 Subcutaneous injection ( 피하투여 ) <Neck, flank or inguinal area can be used> Dose; 1 ml Maximum dose Taut skin: 2 ml/site loose skin:5-10 ml/site

36 Intradermal injection ( 피내투여 ) Dose; 0.2 ml/site is maximum Site; Flank <ID injection with Needle> <ID injection by injector>

37 37

38 <Tarsal Vein> IV injection <Ear vein> Dose: 2.5 ml/kg bolus, 5 ml/kg slow (infusion pump) Continuous IV infusion: 24ml/kg Rate: 1ml/kg/h Site: Ear vein Tarsal Vein

39 IV injection

40 Blood collection ( 채혈 )

41 심전도검사 위치부위방향 LA ( 노랑 ) Proximal of sacrum( 골반 ) I or Dorsal ( 등 ) RA ( 빨강 ) Right mastoid process II or Axial ( 축 ) LL ( 초록 ) Apex of heart, intercostal space of 5-6 rib, close to sternum III or inferior ( 하부 ) <Electrodes placement for surgery>

42 안검사 (Ophthalmology] <Performing the procedure on a conscious and an anesthetized Minipig>

43 Toxicological study with Minipig

44 Classification of Toxicology Pharmacokinetics/Toxicokinetics General Tox Reproductive Tox Safety pharmacology Carcinogenicity Immuno Tox 44

45 General Toxicology Period Species Dosing Route Acute Rodent(Rat/Mice) Single dose toxicity Oral Non-rodent IV Guinea pigs SC Sub-Chronic Rabbits Dogs Cats Minipig Repeated dose toxicity 4 wks repeated Dermal IM IP Intra vaginal/urethral NHP Rectal Chronic 13 wks repeated 26wks repeated Intra vitreal Intra thecal 39 wks repeated Intra articular Carcinogenicity Inhalation 45

46 GLP 독성시험 2 Pharmaco-kinetics (PK) study Male Female Experiences 16 ea PK study (IM) (8 male, 8 female) -2 times 6 ea PK study (PO) (3 male, 3 female) -3 times 6 ea PK study (IV) (3 male, 3 female) -1 times 8 points/24hours Time point 0, 0.5, 1, 2, 4, 8, 12, 24

47 Pharmaco-kinetics (PK) study Group Item Sex No. of Animals Animal No. Volume (ml/kg) Dose (mg/kg) 1 1M G1 3-SL Male 1 1M M F G2 3-SL Female 1 2F F Siallic Lactose PK profile in rodent Siallic Lactose PK profile in Minipig

48 GLP 독성시험 3 Single dose toxicity (GLP certified KFDA) Male/Female (Yucatan, 16ea, 2wk ) Pathology EXP #1 Group VC: 4(2M, 2F) T1: 4(2M, 2F) T2: 4(2M, 2F) Dosing( d1, PO; capsule) T1: 100 mg/kg T2: 300 mg/kg EXP #2 Group VC: 4(2M, 2F) T1: 4(2M, 2F) T2: 4(2M, 2F) T3: 4(2M, 2F) Dosing( d1, PO; capsule) T1: 100 mg/kg T2: 200 mg/kg T3: 300 mg/kg Parameter 1. BW 2. Hematology 3. Serum chemistry 4. Co-agulation 5. Clinical observation 6. Food consumption Necropsy Histopatholgy

49 GLP 독성시험 4 Repeated dose toxicity Male/Female (Yucatan, 16ea, 2wk DRF) Pathology Male/Female (Yucatan, 32ea, 4wk + 2wk recovery) EXP #1 Group VC: 4(2 male, 2 female) T1: 4(2 male, 2 female) T2: 4(2 male, 2 female) T3: 4(2 male, 2 female) EXP #1 Group VC: 4(2 male, 2 female) T1: 4(2 male, 2 female) T2: 4(2 male, 2 female) T3: 4(2 male, 2 female) Dosing( d1~14, IM) T1: 2 mg/kg T2: 10 mg/kg T3: 20 mg/kg Parameter 1. BW 2. Hematology 3. Serum chemistry 4. Co-agulation 5. Clinical observation 6. Food consumption 7. Urinalysis 8. Ophthalmology 9. Electrocardiography Necropsy Histopathology

50 GLP 4 독성시험 Immunogenicity(non-GLP study) Male/Female (Gottingen, 42ea) Pathology/analysis Group Vc: 6(3 male, 3 female) T1: 6(3 male, 3 female) T2: 6(3 male, 3 female) T3: 6(3 male, 3 female) T4: 6(3 male, 3 female) T5: 6(3 male, 3 female) T6: 6(3 male, 3 female) Dosinge( d8, PO;capsule) Vc: Mock vector T1: Commercial Vaccine T2,3,4: A, Asia1, O serotype T5: 3 complex vaccine T6: T5+adjuvant Parameter 1. BW 2. Hematology 3. Serum chemistry 4. Co-agulation 5. Clinical observation 6. Food consumption Necropsy Histopathology Molecular analysis 1. Immunoglobulin G/A 2. Antigen specific IgG 3. TDAR

51 피부독성및유효성시험 유전자치료제의창상회복효능검증

52 Ventral Dorsal 의료기기의유효성평가 Ventral Dorsal 마이크로니들을이용한약물주입후조직병리분석 마이크로니들의피부국소자극평가 Epidermis/Dermis Subcutaneous 마이크로니들이진피콜라젠분포에미치는영향 Epidermis/Dermis Subcutaneous Dorsal Non-treated 1 time 5 times Collagen type I β-actin Ventral Non-treated 1 time 5 times Collagen type I β-actin

(µg/ml) L1 5 L2 10 L3 20 L4 50 L5 100 MIN Ingection Sample Name Nominal Conc.

53 의료기기의유효성평가 니들프리주사기의약물전달효능검증 Needle free injector 를이용한피부약물주입 Biopsy punch 를이용하여피부조직샘플링 커브별추정농도 (ug/ml) Sample Name Nominal Conc. (µg/ml) L1 5 L2 10 L3 20 L4 50 L5 100 MIN Ingection Sample Name Nominal Conc. (µg/g) * * mean SD CV 35.6 MAX Injection Sample Name Nominal Conc. (µg/g) mean SD CV 42.1 약물의조직내분포농도측정

54 What we do in KIT

55 5 Humanized model 면역결핍미니픽모델개발을통한인간화돼지개발

56 5 Diabetes model 인체 Type I/II 당뇨모사미니픽개발 ** ** *

57 5 Osteoarthritis model 퇴행성관절염모델개발및유효성평가

58 Thank you for listening

1장

Thorax CHAPTER 1 (, thorax). (chest) (thorax),. (chest) (pectoral),, () ( ), ( )., (breast). (, thoracic cavity).. ( ) (thoracic cage, rib cage), (, sternum) (, thoracic vertebrae) (, rib) (, costal cartilage)