Farmakokinetične lastnosti in klinična učinkovitost rituksimaba pri bolnikih z difuznim velikoceličnim limfomom B : doktorska disertacija

Rožman, Samo (author), Grabnar, Iztok (mentor), Jezeršek Novaković, Barbara (co-mentor)

Rituksimab je himerno monoklonsko protitelo, ki se specifično veže na antigen CD20, ki se nahaja na površini normalnih in malignih limfocitov B. Dodatek rituksimaba k zdravilom ciklofosfamid, doksorubicin, vinkristin in prednizon (R-CHOP) pomembno izboljša izid zdravljenja bolnikov z difuznim velikoceličnim limfomom B (DVCLB). Odmerjanje rituksimaba je bilo izbrano na podlagi rezultatov kliničnih raziskav, brez natančnega poznavanja njegove farmakokinetike in drugih dejavnikov, ki vplivajo na učinkovitost zdravljenja. Namen dela: Namen raziskovalne naloge je bil ugotoviti, ali obstajajo možnosti za izboljšanje učinkovitosti rituksimaba pri zdravljenju bolnikov z DVCLB. Zato smo izvedli populacijsko farmakokinetično analizo rituksimaba, ki so ga novoodkriti bolniki z DVCLB prejemali v kombinaciji s kemoterapijo CHOP. Ocenili smo povezavo med farmakokinetičnimi lastnostmi rituksimaba in kliničnim izidom zdravljenja ter ovrednotili trajanje odgovora na zdravljenje in celokupno preživetje od začetka zdravljenja do smrti oz. do konca opazovanja. Dodatno smo preverili vpliv štirih najpogostejših polimorfizmov v genih FcγRIIa in FcγRIIIa na učinkovitost zdravljenja z R-CHOP. Materiali in metode: V prospektivno raziskovalno nalogo smo vključili 29 bolnikov z novoodkritim DVCLB. Bolniki so prejeli osem ciklov kemoterapije po protokolu R-CHOP vsake tri tedne. Klinični odgovor smo ocenili v skladu s Chesonovimi kriteriji. Pred in po aplikaciji kemoterapije smo bolnikom vzeli vzorec krvi za določevanje minimalnih in maksimalnih serumskih koncentracij rituksimaba. Določevanje serumskih koncentracij je potekalo na osnovi encimsko-imunskega testa na trdnem nosilcu. Serumske koncentracije rituksimaba smo interpolirali s programom ReaderFit s pomočjo 5-parametrične enačbe na podlagi umeritvene krivulje kalibracijskih standardov. Farmakokinetično modeliranje smo izvedli s programom NONMEM z uporabo rituksimaba pri bolnikih z difuznim velikoceličnim limfomom B. Genotipizacijo za polimorfizme FcγRIIa-27, FcγRIIa-131, FcγRIIIa-48 in FcγRIIIa-158 smo izvedli z verižno reakcijo s polimerazo in sekvenciranjem po Sangerju. Rezultati: Farmakokinetiko rituksimaba je najbolje opisal nelinearni 2-prostorni model s konstantnim in časovno-odvisnim očistkom, kar je v skladu z modelom tarčno posredovane farmakokinetike. Konstantni očistek je bil nižji pri starejših bolnikih in tistih z nižjo telesno maso. Volumen porazdelitve v centralnem prostoru je bil večji pri moških. Bolniki, pri katerih je prišlo do napredovanja bolezni, so imeli počasnejši upad časovno-odvisnega očistka in posledično višji celokupni očistek rituksimaba. Med različnimi genotipi nismo ugotovili statistično značilno različnega odgovora na zdravljenje, preživetja brez napredovanja bolezni ali celokupnega preživetja. Pri bolnikih, ki so bili homozigoti za Val na FcγRIIIa-158, smo opazili trend boljšega odgovora na zdravljenje s kemoterapijo. Zaključek: Poznavanje povezave med serumskimi koncentracijami rituksimaba in kliničnim izidom zdravljenja je nujno, v kolikor želimo izboljšati učinkovitost zdravljenja z rituksimabom pri bolnikih z DVCLB. Podatki kažejo, da na farmakokinetične parametre rituksimaba vplivajo starost, telesna masa in spol, obstaja pa tudi povezava med farmakokinetičnimi parametri in napredovanjem bolezni. Hitrost upada časovno odvisnega očistka bi lahko služila kot napovedni dejavnik uspešnosti zdravljenja z rituksimabom. V raziskavi nismo ugotovili značilnega vpliva polimorfizmov v genih FcγRIIa in FcγRIIIa na odgovor na zdravljenje in preživetje. Rezultati kažejo, da so pri mlajših bolnikih, moških in bolnikih s počasnejšim upadom časovno-odvisnega očistka smiselne dodatne raziskave z večjimi odmerki rituksimaba. Prav tako so potrebne raziskave z večjim številom bolnikov, ki bodo pripomogle k zanesljivejšim odgovorom glede vpliva farmakogenomike na zdravljenje DVCLB.

• Language: Slovenian
• Keywords: difuzni velikocelični limfom B, monoklonska protitelesa, izid zdravljenja, preživetje, genetski polimorfizem
• Work type: Dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: [Ljubljana
• Publisher: S. Rožman
• Year: 2016
• Number of pages: XI, 61 f.
• PID: 20.500.12556/RUL-143780
• UDC: 616-006.44-085(043.3)
• COBISS.SI-ID: 288112640
• Publication date in RUL: 12.01.2023

Secondary language

• Language: English
• Title: Pharmacokinetic properties and clinical efficacy of rituximab in patients with diffuse large B-cell lymphoma : doctoral dissertation

Abstract

Rituximab is a chimeric monoclonal antibody which binds specifically to the CD20 antigen present on the surface of normal and neoplastic B lymphocytes. The addition of rituximab to the chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has significantly improved the clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL). Rituximab dosing schedules were selected based on evidence from clinical practice rather than from consideration of its pharmacokinetics and factors influencing individual exposure. Objective: Pharmacokinetic studies suggest that there is a room for improvement in clinical use of rituximab through a more individualized treatment. The objective of our study was to characterize rituximab pharmacokinetics in 29 newly diagnosed patients with DLBCL treated with R-CHOP. We also evaluated the association of rituximab pharmacokinetics with clinical outcome and estimated the response to treatment and overall survival from beginning of treatment to death or the end of follow-up. Furthermore, we assessed the impact of four most common polymorphisms in the FcγRIIa and FcγRIIIa genes on the response to R-CHOP therapy. Patients, methods and materials 29 patients with newly diagnosed DLBCL were included in this prospective study. Patients received eight cycles of R-CHOP regimen every three weeks. Clinical response was evaluated according to the revised response criteria for malignant lymphoma proposed by International Harmonization Project. Blood was drawn from each patient before and after rituximab infusions to determine its trough and peak serum levels. Serum levels were determined by enzyme-linked immunosorbent assay and interpolated from a standard curve according to a five-parameter logistic curve-fitting program ReaderFit. Pharmacokinetic modelling was performed with non-linear mixed effects modelling software package NONMEM. Genotyping with polymerase chain reaction and sequencing was conducted for FcγRIIa-27, FcγRIIa-131, FcγRIIIa-48 and FcγRIIIa-158 polymorphisms.Results: The data were best described by a nonlinear 2-compartment pharmacokinetic model comprising linear non-specific clearance and time-varying specific clearance component corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Volume of the central compartment was higher in males. Additionally, patients with disease progression had a slower decay of time-varying clearance and therefore higher total clearance. We observed no significant impact of the genotypes on the treatment response, progression-free or overall survival. There was a non-significant trend of better response to chemotherapy in patients homozygous for Val at FcγRIIIa-158 compared to Phe carriers. Conclusion: To improve the efficacy of the treatment of DLBCL it is necessary to understand the association between rituximab serum levels and clinical outcome. In this study, age, weight and gender were shown to affect rituximab pharmacokinetic properties. There was also a correlation between progression of disease and pharmacokinetic parameters. Results indicate that time-changes in clearance could serve as a predictive marker of response to rituximab. We did not observe significant impact of FcγR polymorphism on the response or survival of DLBCL patients. This report demonstrates the rationale for studies evaluating higher doses of rituximab in young patients, males and patients with a slower decay of time-varying clearance. Further studies are also warranted to evaluate the impact of pharmacogenomics in DLBCL patients on the treatment outcome.

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0321
• Name: Napovedni dejavniki poteka bolezni in odgovora na zdravljenje pri raku dojk in drugih rakih