Povezava serumskih koncentracij vedolizumaba in ustekinumaba z izidi zdravljenja pri kronični vnetni črevesni bolezni

Hanžel, Jurij (author), Štabuc, Borut (mentor), R. A. M. D. Haens, Geert (comentor)

Uvod Biološka zdravila so korenito spremenila zdravljenje kronične vnetne črevesne bolezni, saj omogočajo klinično in endoskopsko remisijo bolezni. Raziskave pri zaviralcih tumorje nekrotizirajočega dejavnika alfa (TNF-?), prvih registriranih bioloških zdravilih za to indikacijo, so pokazale, da nekateri bolniki potrebujejo višje odmerke zdravil za doseganje remisije kot drugi. Individualizirano odmerjanje na podlagi meritev serumskih koncentracij zdravil bi lahko vodilo k boljšim izidom zdravljenja. Poleg zaviralcev TNF-? sta za zdravljenje kronične vnetne črevesne bolezni registrirana tudi vedolizumab, zaviralec integrina ?4ß7, in ustekinumab, zaviralec interlevkina-12 in -23. Povezava med serumsko koncentracijo teh zdravil in izidi zdravljenja ni znana. Namen Namen raziskav je bil: - preučiti povezavo med serumskimi koncentracijami vedolizumaba in ustekinumaba ter izidi zdravljenja kronične vnetne črevesne bolezni; - preučiti, ali imajo enkratne meritve serumskih koncentracij ustekinumaba enako napovedno vrednost za izide zdravljenja kot mere kumulativne izpostavljenosti zdravilu (površina pod krivuljo); - razviti farmakokinetski-farmakodinamski model za vedolizumab pri Crohnovi bolezni. Metode Opravili smo prospektivno monocentrično raziskavo pri bolnikih s kronično vnetno črevesno boleznijo, ki so začenjali zdravljenje z vedolizumabom (Crohnova bolezen [CB] in ulcerozni kolitis [UK]) oziroma ustekinumabom (CB). Serumske koncentracije vedolizumaba smo merili neposredno pred vsako infuzijo, serumske koncentracije ustekinumaba smo merili neposredno po prvi intravenski infuziji, nato pa po 2, 4 in 8 tednih. Klinično remisijo smo ocenjevali z vprašalnikom PRO-2 oziroma indeksom Harvey-Bradshaw (v raziskavi z ustekinumabom), endoskopsko remisijo pa z ileokolonoskopijo. V raziskavi z ustekinumabom smo biokemijsko remisijo opredelili s koncentracijo kalprotektina v blatu <100 µg/g. Farmakokinetski-farmakodinamski model smo razvili s podatki iz raziskave LOVE-CD (LOw countries VEdolizumab in CD) z nelinearnim modeliranjem mešanih učinkov. Rezultati V raziskavo z vedolizumabom smo vključili 51 bolnikov (28 s CB, 23 z UK). Mediana koncentracija vedolizumaba po 6 (25.7 proti 15.6 mg/L; P = 0.015) in 22 (15.1 proti 4.9 mg/L; P = 0.001) tednih zdravljenja je bila višja pri bolnikih, ki so dosegli kombinirano klinično in endoskopsko remisijo. Mejna koncentracija 22 mg/L po 6 tednih (površina pod krivuljo 0,733; 95 % interval zaupanja 0,567–0,899) oziroma 8 mg/L po 22 tednih (površina pod krivuljo 0,819; 95 % interval zaupanja 0,692–0,946) sta bili povezani s kasnejšo kombinirano remisijo. V raziskavo z ustekinumabom smo vključili 41 bolnikov s CB. Maksimalne koncentracije ustekinumaba po intravenski infuziji so bile povezane z endoskopsko remisijo (površina pod krivuljo 0,717; 95 % interval zaupanja 0,517–0,916). Šest od trinajstih (46 %) bolnikov s koncentracijami, višjimi od 105 mg/L je doseglo endoskopsko remisijo, medtem ko je endoskopsko remisijo dosegel le en bolnik od štirinajstih (7 %) s koncentracijami, nižjimi od 88 mg/L. Napovedna vrednost meritev v prvih dveh tednih zdravljenja se ni pomembno razlikovala od napovedne vrednosti meritev po 4 oziroma 8 tednih zdravljenja. Prav tako napovedna vrednost kumulativnih mer izpostavljenosti ni bila višja od napovednih vrednosti enkratnih meritev. Razvili smo farmakokinetski-farmakodinamski model za vedolizumab pri CB s podatki prvih 110 bolnikov iz raziskave LOVE-CD. Očistek je bil višji pri bolnikih z nižjimi serumskimi koncentracijami albumina, v prisotnosti protiteles proti vedolizumabu in pri bolnikih, predhodno zdravljenih z biološkimi zdravili. Koncentracija 20,0 mg/L po 22 tednih je bila povezana s 35-odstotno verjetnostjo endoskopske remisije po 26 tednih. Simulacije z modelom kažejo, da bi z intenziviranim odmerjanjem na štiri tedne endoskopsko remisijo lahko dosegli pri 46,5 % bolnikov brez predhodne biološke terapije oziroma pri 40,0 % bolnikov, ki so se že zdravili z biološkimi zdravili. Zaključek Dokazali smo povezavo med serumskimi koncentracijami vedolizumaba oziroma ustekinumaba in izidi zdravljenja. Pomembnejših razlik v napovedni vrednosti različnih mer izpostavljenosti ustekinumabu nismo ugotavljali – maksimalne koncentracije bi torej lahko uporabljali kot zgodnji napovednik uspeha zdravljenja. Farmakokinetski-farmakodinamski model predstavlja osnovo za kasnejše intervencijske raziskave z intenziviranim odmerjanjem vedolizumaba. Klinično uporabnost naših izsledkov lahko potrdijo le intervencijske raziskave.

• Language: Slovenian
• Keywords: kronična vnetna črevesna bolezen, vedolizumab, ustekinumab, farmakokinetika, terapevtsko spremljanje serumskih koncentracij
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2022
• PID: 20.500.12556/RUL-135932
• COBISS.SI-ID: 140565251
• Publication date in RUL: 02.04.2022

HANŽEL, Jurij, 2022, Povezava serumskih koncentracij vedolizumaba in ustekinumaba z izidi zdravljenja pri kronični vnetni črevesni bolezni [online]. Doctoral dissertation. [Accessed 13 April 2025]. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=135932

Secondary language

• Language: English
• Title: The relationship of serum concentrations of vedolizumab and ustekinumab with treatment outcomes in inflammatory bowel disease

Abstract

Introduction Biological drugs have revolutionized the management of patients with inflammatory bowel disease (IBD) by enabling the resolution of symptoms and mucosal healing. Research in tumour necrosis factor alpha (TNF-α) inhibitors, the first biological drugs approved for inflammatory bowel disease, have shown that some patients require higher drug doses to achieve remission than others. Individualized dosing based on serum drug concentrations may lead to better treatment outcomes. In addition to TNF-α inhibitors, two new agents have become available: vedolizumab, an inhibitor of the α4β7, and ustekinumab, an inhibitor of interleukin-12 and -23. The relationship between drug concentrations and treatment outcomes for these agents is not known. Aims We aimed: - to study the association between serum concentrations of vedolizumab and ustekinumab with treatment outcomes in IBD; - to study whether single serum concentration measurements of ustekinumab have the same predictive value for treatment outcomes as measures of cumulative drug exposure (area under the curve); - to develop a pharmacokinetic-pharmacodynamic model for vedolizumab in Crohn’s disease. Methods We performed a prospective single-centre study of patients with IBD starting treatment with vedolizumab (Crohn’s disease [CD] and ulcerative colitis [UC]) or ustekinumab (CD). Serum vedolizumab concentrations were measured at trough prior to each infusion, serum concentrations of ustekinumab were measured immediately after the first intravenous infusion and at week 2, 4, and 8. Symptomatic remission was assessed using the PRO-2 questionnaire or the Harvey-Bradshaw index (in the ustekinumab study) and endoscopic remission with colonoscopy. For patients treated with ustekinumab, biochemical remission was defined as faecal calprotectin <100 μg/g. The pharmacokinetic-pharmacodynamic model was developed from the LOVE-CD study (LOw countries VEdolizumab in CD) with non-linear mixed-effects modelling.   Results We included 51 patients (28 CD, 23 UC) in the vedolizumab study. Median vedolizumab trough concentrations at weeks 6 (25.7 vs 15.6 mg/L; P = 0.015) and 22 (15.1 vs 4.9 mg/L; P = 0.001) were higher in patients with combined symptomatic and endoscopic remission. A threshold of 22 mg/L at week 6 (area under the curve (AUC) 0.733; 95% confidence interval 0.567–0.899) and 8 mg/L at week 22 (AUC 0.819; 95% confidence interval 0.692–0.946) was associated with subsequent combined remission. We included 41 patients (all with CD) in the ustekinumab study. Peak concentrations were associated with endoscopic remission (AUC, 0.717; 95% CI, 0.517–0.916); 6 of 13 patients (46%) with peak concentrations above 105 mg/L (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 mg/L (lower tercile). There was no significant difference between the associations of peak concentrations, week 2 concentrations, AUC through week 2, or later exposure measures (at weeks 4 and 8) with endoscopic or biochemical remission, nor was there an advantage of using cumulative exposure metrics. We developed a pharmacokinetic-pharmacodynamic model for vedolizumab in CD from the first 110 patients participating in the LOVE-CD study. Clearance was higher and vedolizumab exposure lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab and with previous exposure to other biological therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggest that endoscopic remission rates of 46.5% or 40.0% could be reached with every 4 weeks dosing in patients naïve or previously exposed to biological therapy, respectively. Conclusions We demonstrated an exposure-response relationship for both vedolizumab and ustekinumab. There was no significant difference in the strength of association between different ustekinumab exposure metrics and subsequent treatment outcomes – peak concentrations appear to be an attractive early prognostic marker. Our pharmacokinetic-pharmacodynamic model for vedolizumab in CD provides a foundation for future research aiming to maximise endoscopic remission rates with vedolizumab. It should be noted that all these findings require testing in future interventional studies.

• Keywords: inflammatory bowel disease, vedolizumab, ustekinumab, pharmacokinetics, therapeutic drug monitoring