Oligonucleotide Safety Working Group (OSWG), sawv cev los ntawm cov tuam txhab tshuaj xws li AstraZeneca, Novo Nordisk, Cardior Pharmaceuticals, thiab Alnylam Pharmaceuticals, tsis ntev los no tau luam tawm ib daim ntawv dawb qhia txog kev nqus, kev faib tawm, metabolism, thiab excretion (ADME) kev tshawb fawb ntawm oligonucleotide (ADME).
ONs, ntau hom tshuaj uas muaj cov tshuaj sib xyaw ua ke oligonucleotide ib zaug -stranded los yog ob npaug -stranded chains, feem ntau yog los ntawm 12-30 ribonucleotides lossis deoxyribonucleotides, tuav cov lus cog tseg tseem ceeb. Lawv ua haujlwm los ntawm Watson-Crick puag-pairing kev sib cuam tshuam nrog lub hom phiaj nucleotide ib ntus, yog li cuam tshuam rau hauv cov txheej txheem tseem ceeb hauv cellular xws li gene qhia thiab txhais lus los kho cov kab mob ntsig txog cov protein tsis sib xws. Txoj kev kho no suav nrog ntau yam ntawm ONs, suav nrog cov tshuaj tiv thaiv oligonucleotides (ASOs), cuam tshuam me me RNA (siRNA), microRNA (miRNA), me me ua kom RNA (saRNA), aptamers, thiab ribozymes, ntawm lwm tus, nrog ASOs thiab siRNA feem ntau siv.
Txawm hais tias muaj ntau cov lus qhia txog kev tshawb fawb pharmacokinetic, qhov tshwj xeeb ntawm ONs tsim nyog cov tswv yim tsim nyog, raws li cov lus qhia feem ntau tsis ua raws li lawv cov yam ntxwv tshwj xeeb. Hauv kev teb rau qhov sib txawv no, OSWG tau piav qhia tshwj xeebKev tshawb nrhiav ADMECov tswv yim tsom rau kev txhawb nqa kev coj ua zoo tshaj plaws hauv kev txhim kho ONs.
I. Absorption
ONs nthuav tawm cov yam ntxwv tshwj xeeb ntawm qhov hnyav molecular, nqi, thiab hydrophilicity, yuav tsum tau ua tib zoo xav hauv kev tsim qauv. Kev tswj hwm txoj hauv kev rau ONs sib txawv, suav nrog kev tso ntshav (IV), subcutaneous (SC), intrathecal (IT), intracerebroventricular (ICV), inhalation, thiab intravitreal txhaj (IVT).
1. Ib zaug -dose PK Studies:
Ua kev sib caisib zaug - koob tshuaj PK kev tshawb fawbfeem ntau yog tsim nyog rau cov tshiab ONs molecules los tsim kom muaj kev sib raug zoo ntawm cov tshuaj concentrations nyob rau hauv cov ntshav / cerebrospinal kua thiab cov ntaub so ntswg. Txawm li cas los xij, cov platforms uas muaj cov ntaub ntawv keeb kwm yav dhau los yuav ua rau muaj kev xav tau rau cov kev tshawb fawb PK cais, muab qhov zoo sib xws hauv ADME cov khoom ntawm cov tebchaw hauv tib lub platform.
Qhov kev xaiv ntawm txoj kev tswj hwm ua raws li txoj hauv kev kho mob, yuav tsum tsis yog -kev kho mob IV dosing PK cov kev tshawb fawb rau tsis yog - IV txoj kev kho mob los ntsuas qhov bioavailability.
Kev xaiv koob tshuaj tsom iav me me, suav nrog kev txiav txim siab zoo li cov tshuaj siv tshuaj hauv cov tsiaj ua qauv, kev sib txawv scaling, lossis kev siv tshuaj ntau yam.
Kev xaiv tsiaj tsiaj rau cov kev tshawb fawb PK ua ke nrog kev tshawb fawb tshuaj thiab tshuaj toxicological, feem ntau cuam tshuam nrog cov nas thiab primates. Ib leeg- kev tshawb fawb poj niam txiv neej PK txaus, nrog rau kev sib txawv ntawm poj niam txiv neej ntsuas hauv kev rov ua dua tom qab- kev tshawb fawb tshuaj toxicology.
2. Rov ua dua -dose PK/TK Studies:
Pom zoo nyob rau hauv ob qho tib si tsis yog -GLP thiab GLP toxicology kev tshawb fawb,rov ua dua- koob tshuaj PK/TK kev tshawb fawbua raws li cov hauv paus ntsiab lus zoo li me me molecules / biologics. Hnub 1 PK/TK cov ntaub ntawv tuaj yeem hloov pauv ib zaug - cov kev tshawb fawb PK, muab qhov zoo ntawm lub sijhawm, tus nqi, thiab kev txuag tsiaj.
Yuav tsum tau rov ua dua- koob tshuaj PK cov kev tshawb fawb, suav nrog txoj kev tswj hwm, koob tshuaj, kev xaiv hom, qauv matrices, thiab cov txheej txheem tshuaj ntsuam xyuas, ua raws li ib zaug - koob PK.
Kev txiav txim siab ntawm cov ntaub so ntswg ib nrab-lub neej, piv txwv lub sijhawm, thiab koob tshuaj- kev sib raug zoo sib xws yog qhov tseem ceeb hauv kev rov ua dua- koob tshuaj PK / TK kev tshawb fawb, nrog rau kev tshawb nrhiav cov tshuaj tiv thaiv - tshuaj tiv thaiv kab mob (ADA) thaum qhia.
II. Kev faib tawm
Kev faib tawm cov kev sim ua kom paub meej cov ntaub so ntswg thiab lub cev raug, qhia txog lub hom phiaj ntawm lub cev toxicity thiab ntau zaus.
1. Hauv vitro Plasma Protein Binding (PPB) Kev Ntsuam Xyuas:
PPB kev soj ntsuam qhia ONs 'cov yam ntxwv tshwj xeeb khi rau cov ntshav plasma protein, cuam tshuam cov ntaub so ntswg nkag mus thiab kev ua haujlwm tshuaj. Kev hloov kho rau ONs cuam tshuam rau PPB khi, nrog rau kev txiav txim siab txuas mus rau qhov sib txawv ntawm hom thiab kev tswj hwm txoj hauv kev.
2. Nyob rau hauv vivo Tissue Distribution Studies:
Tsis zoo li cov tshuaj biologics ib txwm muaj, kev tshawb fawb txog kev faib cov ntaub so ntswg rau ONs tau ua ua ntej, thaum xaiv cov neeg sib tw, los ntsuas qhov kev xa khoom zoo. Kev kawm tsim tsom iav me me cov tshuaj molecule, yuav tsum tau ua tib zoo xaiv cov hom, koob tshuaj, thiab cov ntsiab lus piv txwv lub sijhawm.
3. Kev txheeb xyuas cov txheej txheem thiab cov ntaub so ntswg sau:
Kev tsim nyog ntau dua li qhov kev lees paub txaus rau cov tshuaj concentration nrhiav kom pom cov hauv kev tshawb fawb cov ntaub so ntswg. Kev txiav txim siab txog kev yuav cov ntaub so ntswg txuas mus rau qhov sib txawv ntawm qhov sib xws ntawm cov tsiaj sib txawv thiab kev xaiv ntawm radiolabeling thiab tsis yog -radiolabeling txoj kev.
4. Kev txiav txim siab tshwj xeeb:
Rau conjugated ONs thiab LNPs, kev ntsuam xyuas dav dav ntawm cov ntaub so ntswg faib yog qhov tseem ceeb, suav nrog kev tshuaj xyuas cov metabolites thiab cov qauv tsim tshiab.
Hauv kev xaus, OSWG daim ntawv dawb ua haujlwm yog lub hauv paus tseem ceeb hauv kev ua kom nkag siab thiab siv cov kev coj ua zoo tshaj plaws hauv ADME tus cwj pwm ntawm ONs cov tshuaj, muab cov kev nkag siab zoo rau kev nqus thiab faib cov txheej txheem tseem ceeb rau kev txhim kho tshuaj zoo.
