Cov tshuaj Oligonucleotide muaj kev txwv qhov nqus ntawm qhov ncauj thiab feem ntau yog siv los ntawm cov kev tsis yog - nkag mus. Lawv feem ntau xa los ntawm kev txhaj tshuaj subcutaneous lossis intravenous, txawm hais tias muaj qee cov lus ceeb toom ntawm kev tswj qhov ncauj. Hauv qee kis, kev kho mob hauv zos tuaj yeem ua tiav los ntawm kev txhaj tshuaj intravitreal lossis intrathecal txhaj tshuaj. Kev nqus ntawm cov tshuaj no yog nrawm, nrog rau qhov siab tshaj plaws plasma concentration hauv 2 mus rau 6 teev.
Cov ntshav concentration nkhaus tom qab txhaj tshuaj ntawm ISIS 104838 [Yu RZ, li al., 2013; Geary RS, et al., 2015].
Lub plasma PK ntawm thib ob- tiam antisense oligonucleotides (ASOs) qhia tau ntau yam -phasic tshem tawm qauv. Cov txheej txheem ntawm kev thauj tshuaj los ntawm kev ncig mus rau cov ntaub so ntswg yog qhov nrawm, ua rau luv luv faib ib nrab - lub neej txij li 0.5 mus rau 3 teev. Cov tshuaj concentration hauv cov ntshav poob sai sai tom qab kev tswj hwm, nrog rau 10-20 npaug txo hauv 4-6 teev thiab 2-4 teev kev txiav txim siab ntawm qhov loj me hauv 24 teev. Thaum noj los ntawm cov ntaub so ntswg, qhov kev tso tawm ntawm cov tshuaj hauv cov ntaub so ntswg yog qeeb heev. Nyob rau theem no, cov tshuaj ntshav ntshav muaj tsawg heev, thiab kev tshem tawm ib nrab-lub neej hauv cov ntaub so ntswg tuaj yeem nyob ntawm 2 lub lis piam mus rau 2 lub hlis. Qhov kev ncua ntev ntawm cov ntaub so ntswg tshem tawm ib nrab-lub neej txhais mus rau lub sijhawm ntev ntawm kev ua ntawm lub hom phiaj. Lub davhlau ya nyob twg tshem tawm ib nrab-lub neej ntawm cov tshuaj nyob rau hauv plasma sawv cev rau nws tshem tawm ib nrab-lub neej nyob rau hauv cov ntaub so ntswg, xav txog cov txheej txheem qeeb ntawm cov tshuaj redistribution los ntawm cov ntaub so ntswg cell mus rau lub extracellular kua thiab plasma compartment. Hauv kev sib piv rau kev faib cov ntshav plasma, cov tshuaj oligonucleotide feem ntau xav tau lub sijhawm ntev dua los faib rau hauv cov hlwb, uas ua rau ncua sij hawm pib ntawm cov tshuaj pharmacodynamic teb txheeb ze rau cov tshuaj concentration.
Cov ntshav plasma trough concentrations (Mean ± SE) tom qab rov ua haujlwm subcutaneous ntawm mipomersen yog raws li hauv qab no:
Dose regimen I: Tom qab 2- lub lis piam dose-loading theem, koob tshuaj ib zaug ib asthiv rau 11 lub lis piam.
Dose regimen II: Siv ib zaug ib lub lim tiam rau 13 lub lis piam (cov pab pawg koob tshuaj 400 mg / lub lis piam tau txhaj rau 10 lub lis piam).
Thov nco ntsoov tias qhov tseeb tus lej ntawm cov plasma trough concentrations tsis tau muab rau hauv cov ntawv koj tau muab. Yog tias koj muaj cov ntaub ntawv tus lej tshwj xeeb, kuv tuaj yeem pab koj suav nrog cov neeg txhais lus.
Vim lawv cov ntaub so ntswg ntev ib nrab -lub neej, cov tshuaj oligonucleotide feem ntau yog siv rau txhua lub lim tiam, txhua hli, lossis txhua xyoo. Piv txwv li, cov tshuaj siRNA lumasiran, tau pom zoo hauv xyoo 2020, tau pib ua haujlwm txhua hli, ua raws li kev noj tshuaj txhua peb lub hlis, txhim kho kev ua raws li tus neeg mob. Tsis tas li ntawd, cov tshuaj oligonucleotide feem ntau pom muaj lub hom phiaj nyob ntev, nrog rau lumasiran, piv txwv li, tswj lub siab ruaj khov lub hom phiaj nyob ntev txog peb lub hlis.
Zoo sib xws PK tus cwj pwm thoob plaws hom [Richard S Geary, 2009].
Tom qab ntau qhov kev tswj hwm, muaj cov tshuaj tsawg tsawg hauv lub cev, feem ntau vim tias cov tshuaj sai sai faib tawm ntawm cov ntshav mus rau cov ntaub so ntswg thiab ua rau cov metabolism hauv cov ntaub so ntswg qeeb. Cov tshuaj Oligonucleotide nce mus txog qhov tsis tu ncua- xeev cov concentrations hauv lub cev kuj maj mam, thiab cov tshuaj tsub zuj zuj ntawm trough concentrations tshwm sim tsuas yog thaum cov tshuaj tau ua tiav tsis tu ncua- xeev hauv cov ntaub so ntswg. Kev ua tiav ntawm kev ruaj khov- lub xeev cov tshuaj ntau ntxiv hauv cov ntaub so ntswg nyob ntawm kev siv ntau zaus thiab cov tshuaj hauv cov ntaub so ntswg tshem tawm ib nrab ntawm - lub neej. Piv txwv li, ib qho tshuaj nrog cov ntaub so ntswg tshem tawm ib nrab- lub neej (kwv yees los ntawm kev tshaj tawm- theem faib hauv cov ntshav) ntawm 2 mus rau 4 lub lis piam yuav siv sij hawm 2 mus rau 4 lub hlis rau trough concentrations hauv plasma kom mus txog qhov ruaj khov- xeev (xav tias tsis muaj cov tshuaj thauj khoom siv). Kev thauj cov tshuaj tuaj yeem ua haujlwm kom nrawm rau lub sijhawm nws siv rau cov tshuaj kom mus txog qhov chaw ruaj khov- lub xeev, tab sis nws tuaj yeem tuaj nrog koob tshuaj - txwv tsis pub muaj tshuaj lom thaum lub sijhawm thauj khoom.
Inter- hom kab mob tsis tu ncua- lub xeev ntshav AUC (chaw nyob rau hauv qhov nkhaus) thiab tus nqi clearance (CL/F) (txhais tau tias ± SD) nyob rau hauv kev sib raug rau mg/kg koob tshuaj (a thiab c) lossis mg/m2 koob tshuaj (b thiab d) [Yanfeng Wang, et al., 2019].
Tsis pub dhau ib koob tshuaj ntau, cov tshuaj oligonucleotide nthuav tawm cov yam ntxwv ntawm cov tshuaj pharmacokinetic hauv plasma. Txawm li cas los xij, nrog kev nce ntxiv hauv koob tshuaj, lawv tso tawm cov tshuaj pharmacokinetics uas tsis muaj kab mob metabolic saturation. Kev txhaj tshuaj subcutaneous ntawm cov tshuaj no ua rau qis qis qis hauv cov ntshav plasma piv rau kev txhaj tshuaj hauv cov hlab ntsha. Txawm hais tias qhov sib txawv ntawm cov tshuaj plasma pharmacokinetics ntawm subcutaneous thiab intravenous kev tswj hwm ntawm tib koob, cov concentrations hauv lub hom phiaj ntawm lub cev yog ze li sib npaug. Pharmacokinetic (PK) cov yam ntxwv ntawm cov tshuaj oligonucleotide muaj feem cuam tshuam nrog lawv cov khoom siv hluav taws xob dav dav, kev hloov kho tshuaj, kev xa tshuaj, thiab cov khoom sib txuas. Cov yam ntxwv ntawm PK no feem ntau ywj siab ntawm nucleotide ib ntus. Piv txwv li, ntau cov tshuaj antisense oligonucleotide nrog cov khoom zoo sib xws ntawm lub cev, xws li cov hloov kho nrog 2'-MOE, qhia txog tus cwj pwm PK zoo ib yam hauv cov nas, dev, liab, thiab tib neeg.
Ob qhov sib txawv nrog tib yam 2'-MOE (2'-methoxyethyl) kev hloov kho pom muaj lub siab thiab lub raum sib txawv ib nrab-nyob tab sis muaj lub siab zoo ib yam-rau-plasma tshuaj concentration piv, uas tseem nyob mus ib txhis [Richard S Geary, 2009].
Thaum lub sij hawm tus txheej txheem ntawm redistribution ntawm cov ntaub so ntswg mus rau plasma, oligonucleotide tshuaj feem ntau tuav ib tug kuj ruaj piv ntawm lawv cov concentrations nyob rau hauv plasma thiab lub siab. Muaj cov ntaub ntawv qhia tau hais tias qhov piv ntawm post- faib cov tshuaj plasma concentration rau daim siab tshuaj concentration rau thib ob - tiam ASOs yog kwv yees li 1: 6000. Qhov piv txwv no tseem nyob ib puag ncig ntawm ntau hom. Qhov no qhia tau hais tias qhov kev raug mob ntawm cov tshuaj nyob rau hauv daim siab cov ntaub so ntswg tuaj yeem kwv yees raws li kev ntsuas cov tshuaj plasma concentration.
Muab kev sib raug zoo ntawm cov ntaub so ntswg cov tshuaj concentrations, trough concentrations, thiab post- faib plasma concentrations, tus yam ntxwv no tseem ceeb heev rau lub tsev.Cov qauv tshuaj pharmacokinetic/pharmacodynamic (PK/PD).. Cov qauv zoo li no tuaj yeem pab daws qhov teeb meem tshwm sim - teb kev sib raug zoo thiab qhia txog kev siv tshuaj.
Cov tshuaj plasma concentration ntawm cov tshuaj nyob rau tom qab-theem kev faib tawm tswj kev sib npaug nrog cov tshuaj qib hauv cov ntaub so ntswg liab [Richard S Geary, 2009].
Qhov raug thiab tshem tawm ntawm ASOs thoob plaws ntau hom sib txawv nrog lub cev hnyav (BW) hauv milligrams ib kilogram (mg / kg) es tsis yog lub cev qhov chaw (BSA). Tus nqi tshem tawm hauv roob ris- noj macaques tuaj yeem ntxiv rau tib neeg ntawm 1: 1 piv raws li lub cev hnyav (mg / kg). Hauv cov nas, qhov kev tshem tawm yog kwv yees li 5-10 npaug siab dua li ntawm tib neeg thaum ntsuas los ntawm lub cev hnyav (qhov ntsuas qhov ntsuas ntawm 7).
Piv txwv li, kev sib txuas ntawm N-acetylgalactosamine (GalNAc) txhim kho lub siab lub hom phiaj ntawm tes, thiab ntawm cov tshuaj muaj feem cuam tshuam, kev nthuav tawm ntawm macaque clearance tus nqi rau tib neeg ua raws li 1: 1 kev sib raug zoo thaum ua raws li lub cev hnyav. Yog tias xam raws li thaj tsam ntawm lub cev (BSA), tus macaque qhov kev tshem tawm yog kwv yees li 30% txog 50% ntawm tib neeg kev tshem tawm. Nyob rau hauv cov nas, siv BW rau scaling muab ib tug zoo kwv yees ntawm tib neeg clearance tus nqi. Thaum ntsuas los ntawm BW, nas clearance yog kwv yees li kaum npaug ntawm tib neeg.
siRNA cov tshuaj raug tshem tawm sai sai ntawm cov ntshav plasma, ua rau lub sijhawm luv luv ib nrab-lub neej hauv ntshav (xws li, 3 hnub rau Patisiran). Txhawm rau txuas ntxiv qhov kev tshem tawm ib nrab-lub neej, kev hloov kho tshuaj xws li GalNAc-siRNA lossis lipid- cov tshuab xa tawm raws li kev ua haujlwm, tso cai rau ib nrab- lub neej uas tuaj yeem ncav cuag ob peb lub lis piam. Qhov no txhawb nqa qhov kev xav tau ntawm kev kho mob rau kev noj tshuaj nyob rau lub sijhawm ntawm lub lis piam lossis peb lub hlis twg.
