Tigecycline Dosing Strategies nyob rau hauv Critically Ⅲ Cov Neeg Mob Tsis Txaus Siab

Xav paub ntau ntxiv plz hu raudavid.wan@wecistanche.com

Abstract: Txoj kev tshawb no tshawb xyuas tigecycline raug rau hauvmob hnyavCov neeg mob los ntawm cov pej xeem pharmacokinetic foundations los txhawb kev noj tshuaj muaj txiaj ntsig hauv chav saib xyuas mob hnyav (ICU) cov neeg mob uas mob siab thiab mob siab. Cov ntaub ntawv kho mob ntawm 39 tus neeg mob tau txais txiaj ntsig los ua lub hauv paus rau kev txhim kho ntawm cov pej xeem pharmacokinetic qauv. Qhov kev tshem tawm ntawm tigecycline raug txo qis (8.6 L / h) piv rau lwm cov neeg. Cov qauv sib txawv tau tsim los ntawm daim siab thiab lub raum ua haujlwm ntsig txog covariates. Monte Carlo simulations tau siv los qhia kev hloov kho koob tshuaj nrog qhov kev kwv yees ntau tshaj plaws: Child-Pugh qhab nia, tag nrho bilirubin, thiab MELD qhab nia. Qhov ua tau zoo tshaj plaws covariate, coj kev txo koob tshuaj rau 25 mg q12h, yog Child-Pugh qhab nia C, thaum cov neeg mob uas muaj tus qhab nia Child-Pugh A / B tau txais tus qauv koob tshuaj ntawm 50 mg q12h. Ntawm qhov kev ceeb toom, qhov tau txais 24 h nyob ruaj khov-xeev cheeb tsam nyob rau hauv qhov concentration vs. time curve(AUCs) range using this dosing strategy was predicted to be similar to high-dose tigecycline exposure (100 mg q12h) in non-ICU. Tsis tas li ntawd, 26/39 cov neeg koom nrog txoj kev tshawb fawb tau tuag, thiab kev kho tsis ua haujlwm feem ntau cuam tshuam nrog cov kab mob siab ntev thiab lub raum tsis ua haujlwm, tab sis tsis muaj kev sib raug zoo ntawm kev siv tshuaj thiab kev ciaj sia. Txawm li cas los xij, tigecycline hauv cov neeg mob tshwj xeeb xav tau kev tshawb nrhiav ntxiv los txhim kho cov txiaj ntsig kho mob.

Ntsiab lus:pej xeem pharmacokinetics; Child-Pugh qhab nia; kev kho tshuaj

Nyem qhov no kom paub ntau ntxiv txog Cistanche

1. Taw qhia

Tigecycline, nyob rau hauv chav kawm ntawm glycylcyclines, yog cov tshuaj tua kab mob zaum kawg thiab tam sim no tau pom zoo rau cov kab mob ntawm daim tawv nqaij thiab cov kab mob ntawm daim tawv nqaij nyuaj (SSI, kab mob sib kis hauv plab (av nplaum), thiab cov kab mob hauv zej zog. Cov kab mob tsis zoo thiab Gram-zoo, nrog rau cov kab mob ntau yam tshuaj tiv thaiv kab mob[1].Tigecycline is considered a bacteriostatic drug that inhibits the bacterial protein translation by binding to the 30S ribosomal subunit [2]. The 24 h steady-state area under the drug concentration vs. time curve(AUCs) to minimum inhibitory concentration (MIC) ratio (AUC/MIC) of >17.9 (SSI) and>6.96(cIAI) piav qhia txog cov tshuaj pharmacokinetic/pharmacodynamic(PK/PD) lub hom phiaj ntawm tigecycline [3,4]. US Food and Drug Administration (FDA) tsis pom zoo tigecycline ua thawj kab kev kho mob rau cov neeg mob uas muaj mob hnyav. Hauv kev tshuaj ntsuam sib piv sib piv tigecycline rau lwm cov tshuaj tua kab mob hauv cov kab mob loj, muaj kev pheej hmoo tuag ntau ntxiv (4 feem pua ​​(15{12}}/3788)vs. 3 feem pua ​​(11{15}}/3646)), qhia tawm tag nrho-ua rau kev tuag ntawm 0.6 feem pua ​​(95 feem pua ​​CI, 0.1 feem pua ​​​​rau 1.2 feem pua) tej zaum yog vim muaj kev kis tus kab mob [5]. Qhov kev tuag ntau ntxiv no tau pom feem ntau nyob rau hauv cov neeg mob tau kho cov ntawv lo rau lub tshuab ua pa uas cuam tshuam nrog mob ntsws [5] thiab ua rau lub thawv dub ceeb toom los ntawm US FDA (1 Cuaj hlis 2010; 27 Cuaj hlis 2013). Txawm li cas los xij, nrog kev nce ntxiv rau cov tshuaj tua kab mob thawj zaug thiab / lossis tsis muaj lwm txoj kev kho mob, tigecycline feem ntau yog ib qho ntawm ob peb lub sijhawm kawg los kho cov kab mob hnyav. Ntxiv nrog rau qhov kev ntsuam xyuas qhov tseeb ntawm qhov qhia, qhov kev pom zoo yog qhov tseem ceeb rau kev sib npaug microbial eradication thiab tolerable phiv. Ntau qhov kev tshawb fawb tau tshaj tawm tias muaj kev tshem tawm cov kab mob microbiological nrog ntau dua tigecycline koob tshuaj [6-10]. Tsis tas li ntawd, cov kev tshawb fawb tau tshaj tawm yav dhau los tau tshaj tawm tias hloov pauv tigecycline pharmacokinetics hauv ICU cov neeg mob [6,11]. Yog li, kev siv tshuaj yuav tsis haum rau cov neeg mob ICU, piv rau cov neeg mob uas tsis muaj mob hnyav. Kev kho koob tshuaj rau cov tshuaj, uas yog metabolized los yog tshem tawm los ntawm covdaim siab, feem ntau yog ua los ntawm kev siv Child-Pugh Score (CPS) kev faib tawm, vim tsis muaj ib qho kev kuaj sim tuaj yeem txiav txim siab lub siab ua haujlwm thiab tshem tawm lub peev xwm. CPS Ameslikas ntsuam xyuas cov kab mob nyob rau hauv daim siab mob thiab feem ntau yog cais raws li mob me, nruab nrab, thiab mob hepatic impairment, sib raug rau cov qhab nia ntawm A(CPSA), B(CPSB), thiab C(CPSC). Cov ntaub ntawv tshuaj tua kab mob tigecycline qhia txog qhov ntau npaum li cas hauv lub siab tsis txaus, qhia tsis muaj kev hloov kho koob tshuaj (100 mg thawj koob, 50 mg q12h, iv) hauv cov neeg mob me lossis nruab nrab (CPSA, CPSB), tab sis kev saib xyuas koob tshuaj txo qis rau 25 mg q12h rau qhov hnyav. cov neeg mob uas tsis muaj CPSC. Tsis tas li ntawd, cov neeg mob cirrhotic muaj kev pheej hmoo siab dua rau cov kab mob Gram-zoo, uas tuaj yeem ua rau lub siab tsis ua haujlwm. Ntxiv rau qhov ntawd, qhov mob hnyav ntawm cov neeg mob no feem ntau nce ntxiv thiab cuam tshuam nrog kev tuag ntau dua [12]. Txawm li cas los xij, kev txiav txim siab noj tshuaj feem ntau cuam tshuam nrog kev tsis paub tseeb. Ntawm qhov tod tes, bilirubin yav dhau los cuam tshuam nrog tigecycline raug tab sis tseem tsis tau siv rau kev kho tshuaj tsis tau [13,14].

Yog li ntawd, cov ntaub ntawv ntxiv yuav tsum tau piav qhia txog cov tshuaj pharmacokinetics ntawm tigecycline hauv cov neeg mob uas mob siab rau lub siab. Yog li ntawd, peb tau ua ib tug pej xeem pharmacokinetic (Popp K) tsom xam ntawm tigecycline nyob rau hauv no tshwj xeeb cov neeg mob cov pej xeem thaum soj ntsuam daim siab-related soj ntsuam kuaj tsis (covariates) siv nonlinear mix-effects qauv. Raws li tus qauv tsim Popp K, Monte Carlo simulations tau siv los tshawb xyuas covariates tsim nyog rau kev hloov koob tshuaj thiab simulation ntawm lub hom phiaj ua tiav.

2. Cov txiaj ntsig

2.1.Study Participants

Txoj kev tshawb no nrhiav tau 39 tus neeg mob, uas tau pab 283 lub sijhawm ntsuas ntshav plasma ntawm tigecycline raupharmacokinetic(PK) qauv tsim. Table 1 qhia txog cov yam ntxwv ntawm tus neeg mob, cov ntaub ntawv kuaj mob, cov kab mob sib kis, nrog rau cov kab mob hauv lub siab. Cov kab mob gram-zoo lossis ntau yam kab mob feem ntau ua rau muaj kab mob. Ob tus neeg mob tau txais kev kho lub raum hloov (RRT), uas tsis suav tias yog ib qho xwm txheej cuam tshuam, raws li kev tshawb fawb yav dhau los tsis pom muaj feem cuam tshuam ntawm RRT ntawm tigecycline PK[13].

2.2. Pharmacommetric Data Analysis 2.2.1.Base Model

Txhawm rau txheeb xyuas cov tshuaj plasma pharmacokinetics, kev ua qauv tsis sib xyaw ua ke tau siv. Ib tug qauv ob chav nrog linear disposition thiab tshem tawm tau piav qhia txog tigecycline plasma pharmacokinetics thiab tau zoo dua rau ib qho qauv sib txuas los piav txog cov tshuaj plasma pharmacokinetics (qhov sib txawv hauv Akaike Cov Ntaub Ntawv Txheej Txheem (dAIC):-397). Qhov seem uas tsis tau piav qhia qhov txawv txav tau piav qhia los ntawm tus qauv kev ua yuam kev sib piv, thiab tsis muaj qhov yuam kev ntxiv (qhov poob ntawm lub hom phiaj ua haujlwm tus nqi (DV): ntxiv rau 206) lossis ib qho kev sib xyaw ua ke thiab cov qauv ua piv txwv muab tus qauv zoo dua fit(dOFV:-0.013). Interindividual variability (IV) tau txais kev txhawb nqa ntawm clearance(CL)(dOFV:-442), central volume of distribution(V.)(dOFV:-48), and the peripheral volume of distribution (Vp) (dOFV:-35). ETA shrinkage yog tsawg li 0 feem pua ​​​​rau CL thiab 13 feem pua ​​​​rau V., qhia tias feem ntau ntawm cov tib neeg tau pab txhawb rau cov kev kwv yees ntawm IIV.ETA shrinkage siab dua rau Vp (43 feem pua), qhia tias qhov kev kwv yees liv no tsis tau txais kev txhawb nqa los ntawm txhua yam. Kev tshawb nrhiav graphical tsom xam thiab kev soj ntsuam qhov cuam tshuam tau coj kev xaiv covariate rau cov txheej txheem kev txheeb xyuas cov txheej txheem. Rau aspartate aminotransferase (AST), alanine aminotransferase (ALT), -glutamyltransferase (GGT), platelet suav, thiab thoob ntiaj teb normalized ratio (INR), tsis muaj qhov sib txawv ntawm tus neeg PK tsis sib piv nrog cov covariates no. Tsis tas li ntawd, peb tsis suav nrog cov ntshav creatine hauv kev tshuaj xyuas covariate, vim qhov kwv yees glomerular filtration rate (eGFR) nqa cov ntaub ntawv ntau ntxiv txog lub raum ua haujlwm. eGFR, tag nrho cov bilirubin (bilirubin rau), qhov siab tshaj plaws lub siab ua haujlwm muaj peev xwm kuaj (Limax test), Tus Qauv rau Kab Mob Siab Kawg (MELDscore), thiab CPS raug kuaj ntawm CL, thiab qhov hnyav, poj niam txiv neej, thiab hnub nyoog ntawm V.were suav tias yog cov muaj peev xwm sib txawv hauv cov pej xeem PKmodel. Nyob rau hauv thawj kauj ruam ntawm cov txheej txheem rau pem hauv ntej inclusion txheej txheem, eGFR, bilirubin rau, CPS, raws li zoo raws li MELD qhab nia ntawm CL, thiab qhov hnyav ntawm Ve yog qhov tseem ceeb covariates thiab txo cov IIV heev (Table 2). Los ntawm qhov pib no, peb cov qauv qauv tsim tau siv ob qho kev sib xyaw covariates (Models A thiab B) lossis txuas ntxiv 'raw covariates (Model C): Qauv A suav nrog CPS raws li categorical covariate ntawm CL los sawv cev rau kev kho mob. Qauv B suav nrog MELD cov qhab nia, thiab Qauv C tau tsim ua raws li cov txheej txheem kev tshem tawm rov qab mus rau pem hauv ntej uas siv cov khoom siv raw tsis suav nrog cov qhab nia sib xyaw Child-Pugh thiab MELD cov qhab nia.

Ford Model A, suav nrog CPS raws li kev sib koom ua ke yog qhov tseem ceeb (dOFV:-11.7) thiab ua rau kev txiav txim qis ntawm tigecycline CL cuam tshuam nrog CPS. CPSC cov neeg mob tau pom 50.1 feem pua ​​​​ txo CL piv rau cov neeg mob uas tau qhab nia ntawm CPSA / B. Tsis tas li ntawd, qhov hnyav ntawm V. yog qhov tseem ceeb (linear, dOFV:-9.9). Kuv raug txo los ntawm 48.2 feem pua ​​​​rau 41.8 feem pua ​​thiab IIVv. los ntawm 85 mus rau 70 feem pua. Ntxiv Table S1 qhia tag nrho cov kev kwv yees zaum kawg ntawm tus qauv ntawd.

Rau Cov Qauv B, MELD cov qhab nia, raws li kev ntsuas sib xyaw ntawm daim siab thiab lub raum ua haujlwm tsis zoo, yog qhov sib txawv tseem ceeb ntawm kev tshem tawm (lub zog, dOFV:-5.45). Kuv raug txo los ntawm 48.2 feem pua ​​​​rau 37.9 feem pua. Kuv raug txo los ntawm 85 feem pua ​​​​rau 69.1 feem pua ​​​​ntawm qhov hnyav ntawm V Qhov kawg qauv tsis muaj nyob rau hauv Cov Lus Ntxiv S2.

Rau Model C, tus qauv kawg suav nrog eGFR (linear, dOFV:{{0}}}.9) thiab bilirubin rau (lub zog, dOFV:-13.5) ntawm CL thiab qhov hnyav (linear, dOFV :-10.1)on Vc. Kuv raug txo los ntawm 48.2 feem pua ​​​​rau 38.3 feem pua ​​thiab IIVv.los ntawm 85 feem pua ​​​​rau 72.4 feem pua. Txo eGFR thiab siab dua bilirubin qhov tseem ceeb sib haum mus rau qis dua CL rau ntau qhov sib txawv. Los ntawm qhov tsawg kawg nkaus mus rau maxi-mum eGFR thiab bilirubin rau tus nqi, CLrange tag nrho yog 5.62-10.5 L / h thiab 4.15-11.0 L / h, raws li. Ntxiv Table S3 qhia txog qhov kawg qauv tsis kwv yees ntawm tus qauv no. Ob qho tib si zoo-ntawm-haum cov phiaj xwm thiab kev kwv yees-kho qhov kev pom kev pom zoo (pc-PVC) tau qhia qhov zoo tag nrho (Cov duab ntxiv S1 thiab S2). Qhov nruab nrab ntawm pc-PVC qhov kev kwv yees thiab kev soj ntsuam zoo tshaj plaws yog overlayed hauv Model A, thiab Model B tau pom qhov nce me ntsis ntawm kev ntseeg siab ntawm 95 feem pua.

Tus qauv zoo tshaj plaws uas tau teev tseg yog Model C nrog AIC ntawm -952 thiab residual unexplained variability (RUV) ntawm 12.4 feem pua, piv rau Model A:-913 thiab Model B:-909. Txawm li cas los xij, MELD cov qhab nia raws li ib qho kev sib koom ua ke ntawm kev tshem tawm (Model B) tuaj yeem txo qhov IIVcu (-10 feem pua) thiab, nrog rau qhov ntawd, rau tib yam li Model A, uas suav nrog ob qhov sib txawv ntawm CL.

2.3. Monte Carlo Simulations

Standard-(100 mg loading dose (LD), 50 mg g12h maintenance dose (MD) thiab low-dose tigecycline(100 mg LD, 25 mg q12h MD)) tau simulated (n =1000). Tshawb nrhiav cov tswv yim hloov kho koob tshuaj thiab qhov tshwm sim ntawm lub hom phiaj kev ua tiav (PTA).Hauv peb cov neeg kawm, qhov kev simulated AUCss qhov tseem ceeb tom qab siv cov qauv siv cov qauv zoo tshaj plaws (Model C) yog 12.4 mg·h / L hauv nruab nrab (2.5th txog 97.5th. th feem pua: 4.10-27.1 mg:h/L) thiab yog li nyob rau hauv thaj tsam ntawm qhov nruab nrab siv AUCsvalues ​​tom qab koob tshuaj ntau ntau tigecycline (100 mg q12h MD) hauv cov neeg mob uas tsis mob hnyav (10.1 mg:h /L, 5. mg q12h, lawv tau nthuav tawm 44.4 feem pua ​​​​nce AUCss thiab 117.5 feem pua ​​​​nce hauv lub xeev Cmin piv rau CPSA / B. Yog li ntawd, tsuas yog 33 feem pua ​​​​ntawm cov neeg mob yuav pw hauv AUCss siv ntau yam vim yog overexposure (Daim duab 1).

Daim duab 1. Simulated AUCssin cov neeg mob nrog Child-Pugh A/B thiab C thiab standard-dose tigecycline (50 mg q12h MD) piv rau simulated AUCss-yw siv ntawm high-dose tigecycline (100 mg q12h MD) nyob rau hauv uas tsis yog mob hnyav. cov neeg mob.

Siv CPSC los qhia txog kev hloov koob tshuaj rau kev noj tshuaj ntawm 25 mg q12h MD pro-vided qhov zoo tshaj plaws kev sib raug zoo nrog AUCss'reference'range, ob qho tib si nyob rau hauv cov nqe lus ntawm kev pom zoo ntawm nruab nrab AUCss thiab cov feem ntawm simulated cov neeg mob dag nyob rau hauv lub 2.5th. thiab 97.5th AUCss ncua sij hawm (Figure2). Rau covariates MELD cov qhab nia, bilirubin, thiab eGFR, qhov kev txiav tawm zoo tshaj plaws rau kev txo koob tshuaj tau pom nyob rau ntawm Ntau dua lossis sib npaug rau 30, Ntau dua lossis sib npaug rau 10 mg / dL, lossis<30 ml/min,="">

Txawm li cas los xij, qhov kev pom zoo ntawm ob qho tib si nruab nrab AUCss thiab cov feem ntawm cov neeg mob pw hauv qhov 'reference' ntau npaum li cas qis dua piv rau thaum siv CPSC los qhia kev hloov koob tshuaj, thiab eGFR tau pom tias ua phem tshaj (Daim duab 2).

Daim duab 2. AUCs los ntawm cov koob tshuaj qis-kho qis tigecycline (25 mg q12h MD) pawg vs. cov pab pawg tsis kho uas tau txais tus qauv-dose tigecycline (50mg q12h MD) hauv peb pawg, piv rau 95 feem pua ​​​​ntawm 100 mg q12h MD tigecycline los ntawm van Wart et al. nyob rau hauv cov neeg mob uas tsis yog-ICU yam tsis muaj kev puas siab puas ntsws hepatic (AUCss-VW, kab ntsug). Qhov kev txiav tawm zoo tshaj plaws rau kev tshuaj xyuas kev kho tshuaj yog CPSC, tag nrho cov bilirubin Ntau dua lossis sib npaug ntawm 10mg / dL, MELD qhab nia Ntau dua lossis sib npaug rau 30, thiab eGFR Tsawg dua lossis sib npaug li 30mL / min.Qhov ntau [feem pua] ntawm cov tib neeg simulated nyob rau hauv 95 feem pua ​​​​ntawm AUCss-saib tau tshwm sim.

2.4.Probability of Target Attainment

The alignment of the probability of PK/PD target attainment vs. MIC curve was highest when using the CPS-guided dosing. Nonetheless, all evaluated dose adjustment strategies pro-vided a high (>90 feem pua ​​) qhov tshwm sim kom ua tiav lub hom phiaj rau cIAI(PTAgoy, AUCss/MIC Ntau dua lossis sib npaug rau 6.96[4) rau cov kab mob uas muaj MIC Tsawg dua lossis sib npaug rau 0.5. Rau lub hom phiaj SSI siab dua (AUCss/MIC Ntau dua lossis sib npaug rau 17.9[3]), PTA90 feem pua ​​​​tau txais cov kab mob nrog MIC Tsawg dua lossis sib npaug rau 0.25 (Daim duab 3). 2.5.Study Outcome

Hauv qhov kev tshawb fawb no, 8/39 cov neeg mob (20 feem pua) tau pom kev kho mob, 5/39 (13 feem pua) kev kho nruab nrab, thiab tsis ua haujlwm tau pom zoo rau 26/39 (67 feem pua) cov neeg mob. Txhawm rau soj ntsuam cov txiaj ntsig kev kho mob, qhov kev tshuaj ntsuam no siv qhov sib txawv sib txawv. Qhov kev sib raug zoo tshaj plaws ntawm kev kho tsis ua haujlwm tau pom tias muaj kab mob siab ntev (LOSSIS: 14.2 CI95 feem pua ​​:8.89-24.3), ua raws li cov ntshav creatinine (OR: 4.55, Cl95 feem pua ​​:3.{19}}. 37), qhov uas qhov tshwm sim ntawm kev kho tsis ua haujlwm tau nce ntxiv nrog kev nce ntshav creatinine. eGFR, xam los ntawm cov mis CKD-EPI, tsis tshua tseem ceeb (LOSSIS: 0.98, Cly59;0.95-0.99), piv rau cov ntshav creatinine nkaus xwb.INR nrog ib qho LOSSIS ntawm 0.36 (CIg5 feem pua ​​​​:0.25-0.51), bilirubin rau (OR: 1.30, CI95 feem pua ​​; 1.22-1.39) thiab MELD qhab nia (OR: 13, CI95 feem pua ​​​​: 1.16) yog qhov tseem ceeb kwv yees ntawm kev tuag. Tsis yog CPSC, AUC24n ntawm tigecycline, los yog cov kab mob ua rau tus kab mob los yog lwm cov ntaub ntawv kuaj tau kwv yees txog kev kho tsis ua haujlwm lossis kev tuag.

Figure 3. Probability of target attainment (PTA) analysis of AUCs/MICratio>17.9 and>6.96 tshaj qhov tsawg kawg nkaus inhibitory concentration (MIC). Kev hloov koob tshuaj (25 mg q12h MD) tau siv rau cov neeg uas muaj bilirubin Ntau dua lossis sib npaug rau 10 mg/dL, MELDscore Ntau dua lossis sib npaug rau 30, thiab eGFR Tsawg dua lossis sib npaug li 30 mL / min thiab muab piv rau cov pab pawg uas tsis yog kho (50 mg q12h MD) cov pab pawg, nrog rau kev hloov kho koob tshuaj Child-Pugh. Kab rov tav dotted qhia txog 90 feem pua ​​​​PTAg0 feem pua.

3. Kev sib tham

Txoj kev tshawb fawb tam sim no tsom los ntsuas qhov cuam tshuam ntawm cov sib txawv covariates ntawm tigecycline raug los ntsuas lawv cov peev xwm siv los ua tus kwv yees rau siab thiab muaj peev xwm ua tau zoo tshaj plaws AUC qhov tseem ceeb thiab lawv lub peev xwm los coj kev hloov kho koob tshuaj hauv lub siab tsis zoo. Cov neeg mob pawg neeg no muaj qhov sib txawv ntawm AUC qhov tseem ceeb, tab sis cov txiaj ntsig tau pom zoo nrog cov kev tshawb pom yav dhau los, tias CPSC muaj peev xwm coj kev txo qis ntawm 50 mg mus rau 25 mg q12h.

Txoj kev tshawb no tau nrhiav ib pawg neeg tsis muaj zog heev nrog kev kho mob tigecycline, uas tsis tau sawv cev zoo hauv cov ntaub ntawv txog tam sim no. Cov neeg mob muaj cov theem sib txawv ntawm kev mob siab thiab mob ntev, ua piv txwv los ntawm kev txo qis heev ntawm CL ntawm 7.52 L / h hauv peb pawg piv rau cov neeg ua haujlwm noj qab haus huv, lwm cov neeg mob ICU (xws li, 18.3 L / h [13], 22.1 L / h [ 15], 13.5 L / h [16]), thiab cov neeg mob uas tsis yog ICU (piv txwv li, CL ntawm 16.8L / h [17] thiab 18.6 L / h [18]). . Undoubtedly, kev nyab xeeb thiab kev kho mob zoo yog yuav tsum tau rau cov neeg mob no. Txawm li cas los xij, kev hloov kho koob tshuaj rau cov tshuaj tua kab mob hepatically yog qhov nyuaj, vim tias qhov kev tshem tawm ntawm lub siab tsis tuaj yeem txiav txim siab los ntawm ib tus cim endogenous nkaus xwb, xws li creatinine tshem tawm raws li tus neeg sawv cev rau kev tshem tawm cov tshuaj rau lub raum [19]. Kev puas siab puas ntsws loj nrog CPSC yog 50.1 feem pua ​​​​thiab yog li nyob rau hauv txoj kab nrog kev tshawb pom ntawm Korth-Bradley li al. leej twg pom CL txo ntawm 50.6 feem pua ​​[20]. Li no, peb cov txiaj ntsig tau lees paub qhov kev pom zoo los ntawm Korth-Bradley li al. siv CPSC los qhia kev hloov koob tshuaj. Tsis tas li ntawd, peb covariate tsom xam pom bilirubin, eGFR, thiab MELD cov qhab nia raws li covariates ntawm CL. Tigecycline tsis yog metabolized nkaus xwb, tab sis feem ntau ntawm cov biliary excreted, piav qhia txog kev sib raug zoo ntawm bilirubin thiab MELD qhab nia rau tigecycline clearance [21]. Ntxiv mus, MELD cov qhab nia tsis ntev los no tau pom zoo rau kev hloov kho koob tshuaj hauv cov neeg mob hnyav, lub siab decompensated, tab sis tsis ncaj qha piv rau CPS [22]. Tsis tas li ntawd, eGFR yog qhov tseem ceeb ntawm cov kev sib txawv hauv peb cov neeg kawm. Lub raum kev ua haujlwm tseem cuam tshuam los ntawm kev kis kab mob siab [23], uas tuaj yeem piav qhia qhov sib cuam tshuam zoo rau kev tshem tawm tigecycline. Korth-Bradley et al.observed 20 feem pua ​​​​tso tseg tigecycline clearance nyob rau hauv tiag tiag impaired kev kawm, tab sis tsis muaj kev hloov koob tshuaj, raws li lub raum clearance account tsuas yog 20 feem pua ​​​​ntawm tag nrho lub cev clearance [24]. Peb qhov kev tshawb fawb tau ua raws li qhov kev tshawb pom no, qhov kev txo qis eGFR muaj zog tsis yog lub teeb liab los kho cov koob tshuaj. Yog li, CPS ua tau zoo tshaj plaws kom sib npaug sib npaug ntawm qhov sib npaug ntawm qhov sib npaug ntawm cov tshuaj tua kab mob (25 mg q12h MD) vs. cov neeg mob uas tsis kho (50 mg q12h MD), thaum tuav qhov sib npaug rau 100 mg q12h tigecycline pom nyob rau hauv cov neeg mob uas tsis yog mob hnyav [ 18]. Txawm li cas los xij, CPSbears qee qhov kev txwv rau kev siv hauv kev kho mob, vim nws yog ib qho ntawm cov kev hloov pauv hauv kev kho mob thiab cov xwm txheej tau txiav txim siab txog kab mob [16,25]. Yog tias CPS tsis muaj, cov qhab nia bilirubin lossis MELD tuaj yeem ua lwm txoj hauv kev los qhia txog kev hloov koob tshuaj.

Cov koob tshuaj hloov kho algorithms tau soj ntsuam hauv qhov kev tshawb fawb no txhawm rau ua tiav qhov kev sib kis zoo sib npaug rau cov koob tshuaj loj heev tigecycline (100 mg q12h MD) hauv cov neeg mob uas tsis yog ICU, raws li ntau qhov kev tshawb fawb tau qhia tias tus qauv koob tshuaj ntawm 50 mg q12h MD tsis txaus. kom ua tiav kev kho mob txhim khu kev qha 6,10,26-28]. Tam sim no EUCAST MIC breakpoints rau cov kab mob enterobacterales thiab Staphylococcus yog<0.5 mg/l="" (http://www.="" eucast.org/clinical="" breakpoints/,="" accessed="" on="" 21="" march="" 2022).="" our="" simulations="" challenge="" this="" breakpoint="" as="" the="" ptaoo%results="" indicate="" sufficient="" target="" attainment="" at="" a="" micof="" 0.5="" mg/l="" only="" for="" the="" clay="" target,="" but="" insufficient="" target="" attainment="" for="" the="" ssi="" target="" even="" under="" high-dose="" tigecycline="" conditions.="" this="" is="" in="" line="" with="" the="" findings="" of="" kispal="" et="" al.,="" who="" concluded="" by="" escalating="" the="" dose="" to="" 150="" mg.v.q12h="" in="" patients="" with="" higher="" mics="">

Cov ntaub ntawv kho mob tau nthuav tawm MELD cov qhab nia thiab lawv cov khoom (bilirubin thiab SCR) los ua pov thawj ntawm kev muaj sia nyob hauv peb pawg. Piv txwv li, ntau dua AUC24 lossis AUCmhvalues ​​tsis cuam tshuam nrog kev kho mob ntau dua, qhia tias lwm yam xws li kab mob hauv lub cev (lub siab), lub cev tsis ua haujlwm, thiab kev kis mob feem ntau cuam tshuam rau tus neeg mob cov txiaj ntsig. Raws li qhov ntawd, kev tshawb fawb yav dhau los ntawm kev siv tigecycline hauv cov neeg mob hnyav cuam tshuam nrog Sequential Organ Failure Assessment qhab nia (SOFA) nrog rau kev kho mob tsis ua haujlwm [6,30]. Thaum kawg, kev sim ntxiv tau lees paub los txhim kho kev nyab xeeb thiab kev ua tau zoo ntawm kev kho mob tigecycline.

Txoj kev tshawb no muaj txiaj ntsig zoo rau kev nkag siab ntawm tigecycline pharmacokinetics hauv cov neeg mob uas muaj ntau qib ntawm daim siab tsis zoo. Raws li lub zog ntawm txoj kev tshawb no, peb cov tib neeg txoj kev tshawb fawb tau nthuav dav dav hauv cov txiaj ntsig covariate: Cov txiaj ntsig zoo sib xyaw yog xav tau rau kev sib txuas ntawm kev sib raug zoo ntawm cov neeg mob covariates nrog PKparameters. Txawm li cas los xij, stepwise covariate qauv paub tias muaj teeb meem nrog kev xaiv tsis ncaj ncees thiab ntau qhov kev sim [31], ua rau tsis paub tseeb hauv covariate parameter kwv yees. Txawm hais tias txoj kev tshawb fawb no sawv cev rau qhov loj tshaj plaws hauv cov neeg mob lub siab ua haujlwm nrog tigecycline monotherapy, tus neeg mob siab dua yuav tsum tau ua kom qhov tseeb ntawm qhov kev kwv yees kom ntxiv dag zog rau cov lus xaus. Raws li lwm qhov kev txwv ntawm txoj kev tshawb no, cov ntaub ntawv tshawb fawb tsis suav nrog kev ntsuam xyuas ntawm encephalopathy, thiab vim li no, qhov sib txawv no tau raug tsis saib xyuas hauv CPS suav. Ntau tus neeg mob tau ua kom lub tshuab ua pa, thiab yog li ntawd, kev ntsuas ntawm encephalopathy yog qhov nyuaj hauv ICU cov neeg mob uas muaj lub siab tsis sib xws. Ntawm qhov tod tes, qhov tshuaj ntsuam xyuas kev hloov kho nrog CPS tau ua pov thawj tias yog qhov muaj txiaj ntsig zoo txawm tias muaj kev cuam tshuam tsis meej.

Lwm qhov kev txwv yog tias tigecycline nws tus kheej tuaj yeem ua rau hepatotoxicity. Txawm li cas los xij, cov neeg mob suav nrog hauv qhov kev tshawb fawb no tau pom tias muaj lub siab tsis zoo ua ntej ua ntej pib kho nrog tigecycline. Ntxiv mus, qhov zaus ntawm tigecycline-induced hepatotoxicity yog tsawg raws li kev nce siab ntawm cov ntshav aminotransferase tshwm sim hauv tsuas yog 2-5 feem pua ​​​​ntawm cov neeg mob [32], thiab tigecycline pharmacokinetics tau ruaj khov nyob rau hauv kev kho mob. Yog li ntawd, nws tsis zoo li qhov pom tias muaj kev cuam tshuam ntau ntawm tigecycline hauv peb pawg yog qhov tshwm sim thiab tsis ua rau lub siab tsis zoo.

4. Cov ntaub ntawv thiab cov txheej txheem

4.1.Patients and Study Design

Cov neeg mob los ntawm kev phais ICU ntawm Charite University Tsev Kho Mob, Berlin, Lub teb chaws Yelemees tau raug xaiv tom qab kev pom zoo rau kev coj ncaj ncees (EA4/022/13). Ib feem ntawm cov ntaub ntawv kho mob nyoos twb tau luam tawm yav dhau los [33], tab sis tsis tau siv rau pej xeem PK qauv lossis rau kev txhim kho koob tshuaj algorithms. Txoj kev tshawb fawb no suav nrog cov neeg laus laus dua 18 xyoo uas muaj lub siab ua haujlwm tsis zoo tom qab sepsis, nrog rau cov neeg mob uas muaj lub siab ua haujlwm ntev. Ntxiv mus, cov kab mob cuam tshuam nrog kev kis kab mob thiab cov txiaj ntsig kho mob tau sau tseg. Txoj kev kho tau txhais tias yog kev daws teeb meem lossis kev txhim kho tseem ceeb ntawm cov cim qhia thiab cov tsos mob ntawm tus kab mob index, xws li tsis muaj tshuaj tiv thaiv kab mob ntxiv lossis kev cuam tshuam ntxiv. Clinical tsis ua hauj lwm txhais tau tias yog kev tuag vim yog kis kab mob ua ntej qhov kawg ntawm kev kho mob, tsis tu ncua los yog rov muaj tus kab mob uas yuav tsum tau muaj kev cuam tshuam ntxiv, los yog kev kho mob nrog cov tshuaj tua kab mob ntxiv rau cov tsos mob ntawm tus kab mob. Tsis tas li ntawd, qhov kev kho mob nruab nrab tau txhais tau tias yog cov ntaub ntawv sim, uas suav nrog kev tuag tsis cuam tshuam txog kev kis tus kab mob, lossis extenuating qhov xwm txheej uas txwv tsis pub cais tawm raws li kev kho lossis ua tsis tiav.

Hauv kev luv luv, cov neeg mob tau txais ib koob tshuaj ntawm 100 mg muab tshuaj raws li 30 min infusion, ua raws li kev noj tshuaj ntawm 50 mg q12h. Raws li tus kws kho mob qhov kev ntsuam xyuas, yim tus neeg mob tau txais cov tshuaj tua kab mob siab heev nrog 100 mg q12h. Cov neeg ua haujlwm kho mob coj mus kuaj ntawm 0.3,2,5,8, thiab 11.5 teev tom qab kev txhaj tshuaj tsawg kawg 36 teev tom qab pib kho. Bioanalytical kom muaj nuj nqis ntawm tigecycline plasma concentrations tau ua, raws li tau piav qhia yav dhau los [34]. Ntxiv nrog rau cov yam ntxwv ntawm tus neeg mob, qhov chaw kuaj mob tsis suav nrog AST, ALT, GGT, SCR, thiab eGFR raws li CKD-EPI cov mis [35], albumin, bilirubin rau, platelet suav, thiab INR. AST thiab ALT tau txais kev pab rau De-Ritis piv xam. Txoj kev tshawb no kuj tau soj ntsuam cov qhab nia MELD, nrog rau kev xeem Limax, uas muab kev ntsuas ncaj qha ntawm lub peev xwm metabolic ntawm lub siab los ntawm phenotyping ntawm CYP1A2metabolism [36] Tsis tas li ntawd, hnub nyoog, poj niam txiv neej, lub cev qhov hnyav, thiab cov xwm txheej ascites, tau sau tseg. CPS tau suav nrog cov tsis muaj bilirubineot, albumin, INR, thiab ascites. Ascites tau muab qhab nia zoo li tsis muaj, me me (Qib 1), thiab nruab nrab (Qib 2). Kev suav cov qhab nia ntawm Child-Pugh xav tias tsis muaj encephalopathy tam sim no, vim cov ntaub ntawv ploj lawm. Tsis tas li ntawd, tsis muaj kev cuam tshuam tshuaj ntawm tigecycline thiab cov kua dej sib npaug tsis tau txiav txim siab. Rau kev ntsuam xyuas cov txiaj ntsig ntawm kev kho mob, qhov kev tshuaj ntsuam no suav cov kev sib txawv tsis sib xws uas siv cov logistic regression rau txhua qhov chaw kuaj mob siab, AUCs ntawm tigecycline, thiab cov kab mob Gram hom.

4.2.Pharmacometrics Analysis

4.2.1.Base Model

Txoj kev tshawb no tau siv cov kev ua qauv sib xyaw ua qauv uas tsis yog-linear sib xyaw ua qauv NONMEM[ICON, Gaithersburg, MD, USA, version 7.5), tswj los ntawm PsN 5.0 (Uppsala University, Sweden), rau kev tshuaj xyuas pej xeem pharmacokinetic [37]. Cov pej xeem PK qauv tau tsim nrog thawj qhov kev txiav txim raws li kev kwv yees nrog kev sib cuam tshuam (FOCE ntxiv rau kuv). Thaum lub sij hawm tsim qauv, sib txawv compartments, thiab residual yuam kev qauv (ntxiv, proportional, thiab ua ke) raug kuaj. Kev sib txawv ntawm tus kheej tau suav tias yog cov log-ib txwm faib thiab kuaj ntawm txhua qhov chaw muag tshuaj, uas yog tigecycline CL, V. inter-compartmental clearance(Q), thiab cov khoom ntim ntawm cov khoom xa tawm (Vp). 4.2.2.Covariate Analysis

Kev tshawb nrhiav graphical tsom xam ua ke nrog kev soj ntsuam qhov cuam tshuam tau coj covariate xaiv. Ib txoj hauv kev ua ntu zus, raws li qhov ntsuas qhov sib piv ntawm qhov sib piv (pem hauv ntej suav nrog: p-tus nqi<0.05, backward="" elimination:="" p-value="" of=""><0.01), was="" applied.="" this="" study="" tested="" continuous="" covariate="" relationships="" such="" as="" power,="" linear,="" and="" exponential="" relationships="" on="" the="" respective="" pharmacokinetic="" parameters.="" in="" addition="" to="" the="" pure="" statistical="" criteria,="" we="" defined="" a="" strong="" iivcl="" reduction="">10 feem pua ​​​​raws li cov lus qhia ntxiv ntawm covariate yuav tsum tau txiav txim siab rau kev soj ntsuam ntawm qhov muaj peev xwm hloov kho.

4.2.3. Kev ntsuam xyuas zaum kawg

Peb tau soj ntsuam cov neeg sib tw ua qauv los ntawm cov qauv duab thiab cov lej (zoo-ntawm-haum cov phiaj xwm, kev kwv yees-kho kev pom kev pom kev pom, poob ntawm lub hom phiaj muaj nuj nqis, thiab qhov sib txawv ntawm Akaike Cov Ntaub Ntawv Txheej Txheem ntawm ob tus qauv sib tw (qis AIC qhia cov qauv zoo dua)). Parameter uncertainty tau soj ntsuam siv lub log-zoo li profileing-based sampling-importance resampling routine (LLP-SIR), ib tug txheej txheem rau kev ntsuam xyuas parameter uncertainty nyob rau hauv me me datasets [38].

4.2.4.Simulations

Monte Carlo simulations (n ​​= 1000) tau siv los simulate low-(100 mg LD, 25 mg q12h MD) thiab standard-dose (100 mg LD, 50 mg q12h MD) tigecycline. Covariates tau rov ua piv txwv nrog kev hloov pauv los ntawm cov neeg koom nrog kev kawm kom paub txog qhov muaj feem cuam tshuam ntawm covariates hauv peb cov neeg kawm. Cov qauv sib tw covariate tau siv rau kev hloov tshuaj. Lub hom phiaj ntawm kev hloov koob tshuaj yog txhais los ntawm AUC24h ntau yam (10.12,5.3-17.4(50th, 2.5th-95th feem pua). mg LD; 100 mg q12h MD) nyob rau hauv cov neeg mob uas tsis yog mob hnyav siv cov ntaub ntawv luam tawm pharmacokinetic los ntawm kev tshawb fawb soj ntsuam ntawm van Wart li al. [18]. Cov txiaj ntsig kev kho mob tau zoo dua li qhov koob tshuaj tus qauv [6-9].

Ntxiv mus, peb tau ua qhov tshwm sim ntawm lub hom phiaj kev soj ntsuam (PTAoo feem pua) siv lub hom phiaj rau kev thov (PTA9o feem pua ​​, nyob ruaj khov AUC24h/MIc Ntau dua lossis sib npaug rau 6.96[4]) thiab lub hom phiaj siab dua SSI (lub xeev ruaj khov AUC24h/ MIC Ntau dua lossis sib npaug rau 17.9 [3]).

5. Cov lus xaus

Txhawm rau kom ua tiav, kev txo qis hauv daim siab mob hnyav rau kev noj tshuaj ntawm 25 mg q12h yog qhov zoo tshaj plaws-coj CPS ua rau AUcssvalues, uas yog sib npaug rau cov neeg uas tsis yog ICU uas tau txais koob tshuaj ntau dua tigecycline (100 mg q12h MD), uas yav tas los hais txog kev txhim kho cov txiaj ntsig. Bilirubintot thiab MELD cov qhab nia tuaj yeem ua lwm txoj hauv kev los qhia txog kev hloov koob tshuaj tab sis tsis zoo rau CPS. Yog li ntawd, kev soj ntsuam yav tom ntej ntawm tigecycline dosing lub tswv yim hauv cov neeg mob uas muaj lub siab tsis zoo yog lav.