Navigating Preclinical Pharmacokinetics: Qhov tseem ceeb rau kev txiav txim siab rau koob tshuaj, pH, thiab kev tsim
Pharmacokinetic (PK)Cov kev tshawb fawb yog lub hauv paus ntawm kev txhim kho tshuaj, muab cov kev nkag siab tseem ceeb rau kev siv tshuaj li cas yog absorbed, faib, metabolized, thiab excreted (ADME) nyob rau hauv lub cev. Qhov "txoj kev taug kev" no ntawm tus neeg sib tw tshuaj txiav txim siab nws qhov ua tau zoo, kev nyab xeeb, noj kom tsim nyog, thiab siv ntau zaus. Yog tsis muaj cov ntaub ntawv PK muaj zog, kev tswj hwm tshuaj zoo ib yam li kev taug kev qhov muag tsis pom kev - kev ua tau zoo yuav raug cuam tshuam, thiab kev pheej hmoo toxicity tuaj yeem nce ntxiv. Cov kev tshawb fawb PK ntseeg tau yog qhov tseem ceeb rau kev paub, kev tshawb fawb- tau tsav kev txhim kho tshuaj.
Hauv kev sim tsiaj PK, kev tswj xyuas kom zoo txog yam xws li kev ntim ntim rau hauv cov hlab ntsha (IV) thiab qhov ncauj (PO) kev tswj hwm, nrog rau kev tsim pH, yog qhov tseem ceeb rau kev ua kom ntseeg tau tias qhov kev sim tau raug thiab txhawb nqa cov qauv kev noj qab haus huv tsiaj. Tsab ntawv xov xwm no piav qhia txog cov hauv paus ntsiab lus ntawm PK cov kev tshawb fawb, txhawm rau coj cov kws tshawb fawb, tshwj xeeb yog cov neeg ua haujlwm tsis tu ncua hauv chav kuaj, kom nkag siab txog cov ntaub ntawv xav tau thiab kev hloov kho tsim nyog rau kev tswj hwm tshuaj zoo thiab kev sib cais. NtawmPrisys Biotech, peb paub txog qhov tseem ceeb ntawm cov kev txwv no hauv kev tsim cov ntaub ntawv zoo tshaj -, txhais tau cov ntaub ntawv preclinical.
Pom zoo Dosing Volumes thoob plaws hom
Qhov tsim nyog ntim ntim rau kev tshawb fawb preclinical feem ntau yog raws li feem pua ntawm tus tsiaj lub cev hnyav. Feem ntau, ntim yog nyob ib ncig ntawm 1.0% ntawm lub cev hnyav lossis qis dua (piv txwv li, 0.5%). Intravenous (IV) kev tswj hwm, ua ntau tshaj li qhov ncauj (PO) kev tswj hwm, feem ntau siv cov ntim me me, feem ntau nyob ib ncig ntawm 0.5% ntawm lub cev qhov hnyav, uas yog tsawg dua li 1% rau PO dosing.
Txawm hais tias muaj kev zam -piv txwv li, yog tias cov tshuaj muaj qhov tsis zoo solubility thiab cov koob tshuaj ntau yuav tsum tau ntsuas qhov raug, qhov ntim yuav qee zaus nce mus txog 2% ntawm lub cev qhov hnyav- feem ntau qhov no tsis pom zoo. Kev tswj hwm qhov ntim loj tuaj yeem ua rau muaj kev phom sij rau tsiaj thiab ua rau muaj kev txhawj xeeb txog tsiaj txhu.
Table 1: Pom zoo siv ntau tshaj qhov ntim rau ntau hom
| Hom | Qhov hnyav (mL / kg) | Kwv yees li. % Lub cev hnyav | Sau ntawv |
| Nas | 10 ml / kg | 1% | Feem ntau 5-10 mL / kg; lub plab me me, kev pheej hmoo ntawm kev mob plab / aspiration |
| Rat | 10 ml / kg | 1% | Feem ntau 5-10 mL / kg; zoo tshaj plaws ntawm lub plab khoob |
| Aub | 5-10 ml / kg | 0.5-1% | Cov tsiaj loj tuaj yeem tiv taus txog li 15 mL / kg |
| Tsis yog -Human Primate (NHP) | Tsawg dua lossis sib npaug li 5 mL / kg | 0.5% | Sensitive to volume; >5 mL / kg tau yooj yim induce emesis |
Piv txwv (Nas): IV: 1 mg / kg hauv 5 mL / kg ntawm tus Tsov tus tw vein txhaj; PO: 10 mg/kg hauv 10 mL/kg ntawm qhov ncauj gavage.
Xam Xaj Tshuaj Cuam Tshuam rau Kev Siv Tshuaj
Cia peb suav cov tshuaj xav tau rau cov koob tshuaj PO ntawm 10 mg / kg hauv nas hnyav 25g, siv tus qauv koob tshuaj ntawm 10 mL / kg:
Dose rau tsiaj:10 mg/kg * 0.025 kg=0.25 mg
Volume per tus tsiaj:10 mL/kg * 0.025 kg=0.25 mL
Yuav tsum tau Concentration (C):
- (Dose/kg) * Tsiaj Nyhav=C * (Volume/kg) * Tsiaj Nyhav
- 10 mg/kg=C * 10 mL/kg
- C=1 mg/mL
Rau ib pawg PK kawm ib txwm ntawm peb nas:
- Tag nrho cov tshuaj xav tau (yam tsawg kawg nkaus):10 mg / kg * 0.025 kg / nas * 3 nas=0.75 mg.
Qhov no qhia tau hais tias qhov tseeb ntawm cov ntawv xeem siv rau kev kawm PO PK hauv nas tuaj yeem yog me me.
Yog tias peb xav txog qhov koob tshuaj IV ntawm 1 mg / kg, qhov koob tshuaj yog ib nrab (0.5% lub cev hnyav, piv txwv li, 5 mL / kg rau nas). Qhov xav tau concentration yuav yog:
- C=(1 mg/mL / 10 mL/kg) * 2=0.2 mg/mL (xav tias qhov "10" yog hais txog tus qauv dilution factor lossis cov ntsiab lus zoo sib xws los ntawm cov lus piv txwv qub).
Kev suav ncaj qha ntxiv: 1 mg / kg hauv 5 mL / kg=0.2 mg / mL.
Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cov kev suav no sawv cev rau cov khoom siv tsawg kawg nkaus hauv qhov zoo tagnrho, tsis muaj - khib nyiab. Hauv kev xyaum, Cov Koom Haum Tshawb Fawb Cov Ntawv Cog Lus (CROs) nyiamPrisys Biotechfeem ntau xav tau cov khoom siv ntxiv me ntsis (piv txwv li, nyob ib ncig ntawm 3 mg) kom paub meej qhov tseeb ntawm qhov hnyav thiab kev npaj cov khoom noj. Ib qho ntxiv 2-3 mg tej zaum yuav xav tau los tsim LC-MS/MS calibration curves. Rau kev tshawb nrhiav PK ncaj nraim, kwv yees li 5-7 mg ntawm cov ntawv xeem feem ntau txaus.
Tswj kev tsim pH: cuam tshuam rau Solubility thiab ruaj khov
Lub pH ntawm cov tshuaj formulation ho cuam tshuam nws solubility thiab stability. Lub plab pH hauv cov tsiaj yoo mov yog feem ntau ntawm 1.5 txog 3.5. Ntau tus neeg sib tw tshuaj niaj hnub no muaj cov pab pawg ua haujlwm yooj yim, tso cai rau kev txhim kho solubility los ntawm kev hloov pauv pH (acidification). Txawm li cas los xij, aggressively nrhiav solubility los ntawm formulating ntawm huab pH qhov tseem ceeb (xws li acidic los yog heev alkaline) yuav ua rau mucosal puas los yog emesis.
Table 2: Pom zoo pH ntau yam rau kev daws cov tshuaj hauv ntau hom
| Hom | Pom zoo pH Range | Kev txiav txim siab tshwj xeeb |
| Nas | 3.0-8.0 | Tsis txhob muaj acidic (pH<2.5) or alkaline (pH>9) |
| Rat | 3.0-8.0 | Nyob ze nruab nrab (pH 6-7) yog qhov nyab xeeb tshaj plaws |
| Aub | 4.0-8.0 | Tsawg dua rau acidity; tsis txhob pH<3.0 |
| Tsis yog -Human Primate (NHP) | 4.0-8.0 | Zoo ib yam li tib neeg; pH 5-7 yog qhov zoo tshaj plaws |
Kev xav txog kev tsim qauv ntxiv
- Hypertonic Solutions:Yog tias qhov kev xaiv xaiv yog hypertonic (piv txwv li, muaj cov tshuaj osmotic siab zoo li PEG), qhov ntim tshuaj yuav tsum raug txo kom txo qis qhov tshwm sim tsis zoo.
- Co-cov kuab tshuaj: Co-solvents like DMSO at concentrations >10% tuaj yeem ua rau ulceration (5% DMSO feem ntau suav hais tias muaj kev nyab xeeb). Yog li ntawd, nws yog ib qho tseem ceeb kom tsis txhob irritating kuab tshuaj nyob rau hauv formulations npaj rau hauv vivo tswj.Prisys Biotechmuaj kev paub dhau los hauv kev tsim cov qauv tsim nyog rau ntau txoj hauv kev thiab hom.
Xaus: Ua kom muaj zog thiab ncaj ncees Preclinical PK Studies
Ua tib zoo saib xyuas cov ntim ntim, kev tsim pH, thiab kev xaiv cov khoom noj yog qhov tseem ceeb rau kev ua tiav ntawm kev tshawb fawb tshuaj pharmacokinetic preclinical. Ua raws li hom- cov lus pom zoo tshwj xeeb tsis tsuas yog ua kom cov ntaub ntawv muaj txiaj ntsig zoo thiab muaj tseeb tab sis tseem txhawb nqa cov qauv siab tshaj plaws ntawm kev noj qab haus huv tsiaj. Los ntawm kev nkag siab txog cov ntsiab cai tseem ceeb no, cov kws tshawb fawb tuaj yeem ua kom zoo dua lawv cov qauv kev kawm, txo qis qhov sib txawv, thiab pab txhawb kev txhais lus zoo ntawm cov neeg sib tw tshuaj los ntawm lub rooj ntev zaum mus rau lub tsev kho mob.
NtawmPrisys Biotech, peb pab neeg mob siab rau tau zoo- tau dhau los ntawm cov ntsiab lus tsis txaus ntseeg ntawm preclinical PK txoj kev kawm tsim thiab ua tiav, muab cov kws tshaj lij kev txhawb nqa kom ntseeg tau tias kev ncaj ncees thiab kev txhais lus ntawm koj qhov kev tshawb fawb.
