1. Cov kev tshawb fawb nonclinical suav nrog dab tsi?
Teb:Nonclinical thwmsim muaj xws li kev tshawb fawb tshuaj, kev ntsuam xyuas toxicity, toxicokinetics thiab nonclinical pharmacokinetics thwmsim, kev ntsuam xyuas toxicity genotoxicity, carcinogenicity, thiab lwm yam kev ntsuam xyuas (phototoxicity, dependence, immunotoxicity), thiab lwm yam. Rau qee qhov kev faib ua feem siab (ntau dua 10% ntawm tag nrho cov kab mob kis tau thiab qhov kis tau tus mob hauv kev tshawb fawb tsiaj yog qis dua tib neeg raug), nws yuav tsum tau ua cov kev tshawb fawb txog kev nyab xeeb ntawm cov metabolites.
2. Lub hom phiaj ntawm kev soj ntsuam kev nyab xeeb uas tsis muaj chaw kho mob yog dab tsi?
Teb:Lub hom phiaj ntawm kev soj ntsuam kev nyab xeeb uas tsis yog kev kho mob feem ntau suav nrog elucidating toxicity cov tshuaj tiv thaiv cov yam ntxwv ntsig txog lub hom phiaj ntawm lub cev, koob tshuaj tiv thaiv, kev sib raug zoo, thiab muaj peev xwm thim rov qab. Cov ntaub ntawv no tuaj yeem siv los kwv yees qhov kev nyab xeeb pib koob tshuaj thiab ntau npaum li cas rau tib neeg kev sim tshuaj (raws li tau hais ua ntej, NOAEL yuav tsum tau txais hauv kev sim tshuaj toxicology rau kev suav MRSD, qhov siab tshaj plaws tau pom zoo pib koob tshuaj), thiab txiav txim siab soj ntsuam kev soj ntsuam rau qhov muaj feem cuam tshuam tsis zoo.
3. Cov kev tshawb fawb uas tsis yog kev kho mob dab tsi uas yuav tsum tau ua rau thawj zaug - hauv - kev sim tib neeg?
Teb:Rau lo lus nug no, nws yog thawj zaug uas yuav tsum tau qhia meej txog hom tshuaj. ICH M3 (R2) muaj feem xyuam rau cov xwm txheej tshwm sim hauv kev txhim kho tshuaj thiab muab cov ntsiab lus qhia dav dav. Rau biologics, kev tshawb fawb tsis muaj tshuaj kho mob yuav tsum tau ua raws li cov cai ntawm ICH S6.
⑴Pharmacokinetics:Ua ntej IND xa tawm, cov ntaub ntawv ntawm cov metabolism hauv cov khoom tshawb nrhiav hauv ntau hom thiab cov ntaub ntawv hauv vitro metabolism hauv tib neeg, nrog rau cov ntshav plasma protein binding tus nqi, txaus. Cov ntaub ntawv hais txog kev nqus, kev faib tawm, hauv vivo metabolism, thiab kev tso tawm yuav tsum ua kom tiav ua ntej loj - ntsuas kev soj ntsuam (feem ntau yog theem 3). Kev sim PK nqus tau feem ntau ua rau ntau hom ua ntej IND xa thiab kev txiav txim siab PCC kom nkag siab zoo dua PK cov yam ntxwv ntawm cov tshuaj hauv ntau hom, txawm hais tias nws tsis tas yuav tsum muaj ntawm no, uas yog qhov txawv me ntsis.
⑵Kev Nyab Xeeb Pharmacology:Kev soj ntsuam ntawm cov teebmeem ntawm cov hlab plawv, lub hauv nruab nrab lub paj hlwb, thiab cov hlab ntsws yuav tsum ua kom tiav ua ntej IND xa, uas yog kev sib xyaw ua ke ntawm kev ntsuas kev nyab xeeb ntawm cov tshuaj. Cov kev sim tshuaj muaj kev nyab xeeb ntxiv tuaj yeem ua tau thaum lub sijhawm kuaj mob yog tias tsim nyog.
⑶Rov ua dua koob tshuaj toxicity:Feem ntau, ib qho luv luv - lub sij hawm kuaj mob toxicity yog teem raws li qhov kev siv tshuaj thaum ntxov ntawm IND. Yog tias lub sijhawm noj tshuaj yuav tsum tau txuas ntxiv tom qab, yuav tsum tau siv sijhawm ntev dua - kuaj tshuaj toxicity ntev los pab txhawb nws.
⑷Genotoxicity:Nrog tus nqi qis, genotoxicity kuaj ua ke tuaj yeem ua tiav ua ntej IND xa.
⑸Carcinogenicity:Kev kuaj Carcinogenicity yuav tsum ua kom tiav ua ntej kev pom zoo tshuaj.
⑹Reproductive Toxicity:Kev soj ntsuam thiab kev ntsuam xyuas ntawm lub cev xeeb tub yuav tsum tau muab tso rau hauv kev tshuaj ntsuam xyuas tshuaj toxicity ua ntej IND xa mus rau qhov kev ntsuam xyuas ua ntej kev ua me nyuam toxicity, nrog rau kev tiv thaiv nruj hauv kev sim tshuaj txaus. Phase I/II kev tshawb fawb txog kev ua me nyuam muaj kuab lom yuav tsum ua kom tiav ua ntej loj - kev sim tshuaj ntsuam xyuas, thiab Phase III kev tshawb fawb txog kev xeeb tub yuav tsum ua kom tiav ua ntej kev pom zoo.
⑺Phototoxicity:Kev ntsuam xyuas Phototoxicity yuav tsum ua kom tiav ua ntej IND xa. Yog tias cov molar absorptivity ntau dua 1000 M-1cm-1, nws raug pom tias muaj kev pheej hmoo ntawm phototoxicity, thiab kev ntsuam xyuas phototoxicity yuav tsum tau ua ua ntej kev sim tshuaj loj.
4. Yuav ua li cas cov koob tshuaj yuav tsum tau teem rau hauv toxicology kuaj? Yuav xaiv koob tshuaj ntau npaum li cas?
Teb:Hais txog "Txoj Cai Qhia Txog Kev Siv Tshuaj Txhaum Tshuaj Txhaum Tshuaj Txhaum Cai," "Hauv paus ntsiab lus, koob tshuaj siab yuav tsum ua kom pom tseeb cov tshuaj lom neeg hauv cov tsiaj, koob tshuaj tsawg yuav tsum sib npaug lossis siab dua li koob tshuaj zoo hauv cov tsiaj lossis kev siv tshuaj kho mob, thiab cov koob tshuaj nruab nrab yuav tsum tau teem sijhawm nruab nrab ntawm cov koob tshuaj siab thiab cov koob tshuaj qis raws li kev soj ntsuam cov tshuaj lom neeg thiab kev sib raug zoo {0} toxicity."
Hauv kev xyaum, txiav txim siab tus nqi kim ntawm kev kuaj tshuaj toxicology, ua qhov ntau npaum li cas - nrhiav kev kuaj (DRF) nrog ob peb yam tsis yog - tib neeg primates yog tus nqi tshaj plaws - siv tau thiab ua haujlwm - txoj kev txuag. Cov koob tshuaj rau DRF yuav tsum tau teem ntxiv raws li kev tshawb fawb txog kev nyab xeeb ua ntej ua thaum ntxov PCC kev txiav txim siab thiab kev tshawb fawb tshuaj. Ntau lub tsev kawm tam sim no tseem ua cov tshuaj lom neeg mob hnyav nrog rau kev sim DRF, uas tsis yog -GLP kev xeem, raws li tau hais hauv M3 (R2), ua raws li 3R txoj cai los txo kev siv tsiaj.
Rau cov pab pawg tsawg, nruab nrab, thiab siab, qhov sib nrug ntawm 2-3 zaug feem ntau yog siv. Hauv kev sim tshuaj toxicology, qhov xwm txheej zoo tshaj plaws yog tias pawg koob tshuaj siab tuaj yeem ua rau pom pom muaj kev lom zem, thiab cov pab pawg qis lossis nruab nrab siv tau los ua NOAEL.
Tsis tas li ntawd, rau kev xaiv cov koob tshuaj ntau tshaj, M3 (R2) kuj muab cov lus teb tus qauv. Hauv cov ntsiab lus yooj yim, cov koob tshuaj ntau tshaj plaws hauv toxicology yuav tsum yog qhov siab tshaj plaws (MTD) lossis qhov siab tshaj plaws ua tau (MFD, uas tuaj yeem nkag siab tias qhov siab tshaj plaws uas tsiaj tuaj yeem zam tau raws li cov khoom lag luam thiab cov yam ntxwv ntawm cov tsiaj), lossis nws yuav tsum ua kom muaj kev sib kis, lossis qhov raug mob yuav tsum siab txaus (nce txog 50 npaug ntawm qhov kev npaj khomob). Feem ntau, 1000 mg / kg / hnub yog suav tias yog qhov txaus tshwj tsis yog tias cov tshuaj tau npaj kho mob nce mus txog 1g / hnub, thiab qib kis ntawm 1000 mg / kg tsis ncav cuag 10 npaug ntawm qib kev kuaj mob, nyob rau hauv rooj plaub uas koj yuav tsum tau nce koob ntxiv mus rau 10 npaug ntawm qhov chaw kuaj mob, lossis 2000 mg / kg.
5. Cov kev tshawb fawb twg hauv kev tshawb fawb txog kev nyab xeeb uas tsis muaj chaw kho mob yuav tsum ua raws li GLP, thiab qhov twg tsis yog?
Teb:Pharmacological thiab pharmacokinetic cov kev tshawb fawb tsis tas yuav ua raws li GLP, thaum muaj kev nyab xeeb pharmacology, genotoxicity, kev ua me nyuam toxicity, thiab rov tshuaj toxicity kev tshawb fawb yuav tsum tau ua raws li GLP.
6. Lub sij hawm ntev npaum li cas ntawm kev tshawb fawb txog tshuaj toxicity uas tsis muaj tshuaj kho dua tshiab?
Teb:Lub sijhawm yuav tsum muaj rau kev txhawb nqa kev sim tshuaj xyuas thiab kev pom zoo ua lag luam sib txawv thiab yuav tsum tau tshwj xeeb rau lub sijhawm siv tshuaj ntawm kev sim tshuaj. Piv txwv li, rau cov neeg mob uas muaj ntau yam sclerosis, qhov tsawg kawg nkaus npaj kho mob lub sijhawm sim yog ob xyoos. Yog li ntawd, thaum tso npe rau ntau tus neeg mob sclerosis hauv kev sim tshuaj, yuav tsum muaj 6-hli nas thiab 9-hli tsis- nas mob toxicity kev tshawb fawb, uas yog txaus los txhawb kev lag luam pom zoo. Rau cov tshuaj uas tsis yog -oncology, 4-lub lim tiam kev tshawb fawb txog kev mob toxicity feem ntau yog siv los txhawb lub sijhawm siv tshuaj tsis pub dhau 4 lub lis piam rau kev sim tshuaj thawj zaug hauv tib neeg.
7. Yuav ua li cas xaiv cov tsiaj sim rau kev soj ntsuam kev nyab xeeb uas tsis yog kev kho mob?
Teb:Feem ntau, ob hom tsiaj siv, nas nrog nas yog qhov nyiam xaiv, thiab tsis yog - nas nrog Beagle dev yog qhov nyiam xaiv. Tau kawg, cov khoom tshwj xeeb- cov qauv kev tshuaj xyuas tshwj xeeb yuav tsum tau ua raws. Rau me me molecules, kev xaiv ntawm hom yuav tsum tsuas yog xav txog cov yam ntxwv metabolic ntawm cov khoom tshawb nrhiav hauv cov tsiaj uas zoo ib yam li tib neeg. Kev siv tau tuaj yeem ua rau "Kev Ntsuam Xyuas thiab Kev Ntsuas Kev Ntsuas ntawm Metabolites ntawm Kev Tshawb Fawb Cov Khoom hauv CD-1 Mice, SD Rats, Beagle Dogs, Cynomolgus Monkeys, thiab Human Liver Microsomes", xaiv hom tsiaj uas muaj cov yam ntxwv metabolic zoo ib yam li tib neeg, uas yog, hom tsiaj uas muaj cov txiaj ntsig zoo sib xws thiab hom metabolites rau tib neeg. Tsis tas li ntawd, cov kab uas tau xaiv yuav tsum tau nkag siab rau cov khoom tshawb nrhiav. Raws li kev paub dhau los, rau cov tshuaj molecule me me, nws cov yam ntxwv metabolic hauv Beagle dev yuav zoo ib yam li tib neeg tab sis tsis tshua muaj tshwm sim.
