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Souhrn: Úvod: Cílem práce bylo měření hladin infliximabu (IFX) a adalimumabu (ADM) u pacientů s idiopatickými střevními záněty, zhodnocení vlivu měření farmakokinetiky na způsob optimalizace léčby, korelace hladin bio logik s vybranými parametry a porovnání dvou laboratorních metod ke stanovení hladin IFX. Metody: Do souboru pacientů byli zařazeni pacienti s Crohnovou nemocí a ulcerózní kolitidou léčení IFX nebo ADM ve FN Ostrava v období od 1/2016 do 10/2019. U všech pacientů byla stanovena hladina bio logika a případný výskyt protilátek proti němu, dále byly hodnoceny důležité klinické a laboratorní ukazatele. Pro měření hladin bio logických léčiv byla využita metoda ELISA (enzyme-linked immunosorbent assay) a imunochromatografická metoda v režimu POCT (point of care testing). Získaná data byla podrobena statistické analýze. Výsledky: Hladina IFX < 3 mg/l byla přítomna u 43,9 %, v rozmezí 3–7 mg/l u 38,6 % a > 7 mg/l u 17,5 % pacientů. Protilátky proti IFX byly přítomny u 7 % pacientů. U ADM byla situace příznivější – hladina < 4 mg/l byla u 18,5 %, mezi 4 a 8 mg/l u 52,6 %, > 8 mg/l u 28,9 % pacientů a protilátky proti ADM byly nalezeny jen u 5,3 % pacientů. Analýza byla zaměřena na zjištění závislosti mezi sledovanými faktory a hladinou léku v krvi pacienta. Statisticky významný negativní vliv na hladinu ADM měla hmotnost pacienta, negativní vliv na hladinu bio logik vykazovala i délka jejich podávání. Podíly optimalizací léčby byly následující: intenzifikace 56 %, switch 12 %, swap 8 %, úprava konkomitantní terapie 8 %, ukončení terapie 12 %, deeskalace dávky 4 %. Úpravou léčby bylo dosaženo klinické remise ve 47,6 %, dalších 33,3 % získalo terapeutickou odpověď. Pacienti s ukončenou terapií setrvávají v remisi, pacientka po deeskalaci dospěla k relapsu. Nebyly shledány statisticky významné rozdíly hladin získaných imunochromatografickou POCT a ELISA metodou. Případné kazuistické klinicky významné rozdíly byly dány pravděpodobně lidským faktorem. Závěr: Reaktivní terapeutické monitorování koncentrace léčiv (TDM – therapeutic drug monitoring) se stalo již nedílnou součástí naší klinické praxe a je široce využíváno. Představuje racionální základ optimalizace biologické léčby. Otázkou zůstává budoucnost proaktivního TDM, zejména ochota plátců zdravotní péče akceptovat tento přístup.

Summary: Introduction: This study was designed to measure infl iximab (IFX) and adalimumab (ADM) levels in patients with non-specific inflammatory bowel disease, to evaluate the influence of pharmacokinetics monitoring on optimization of treatment, to correlate the concentrations of these biologics with selected parameters, and to compare two laboratory methods of measuring IFX concentrations. Methods: Patients with Crohn’s disease and ulcerative colitis, who were treated with IFX or ADM at the University Hospital of Ostrava between 1/2016 and 10/2019, were evaluated. Concentrations of biologics were measured in all patients using immunochromatographic methods, including enzyme-linked immunosorbent assay (ELISA) and point of care testing (POCT). Other demographic and clinical characteristics were measured, as were antibodies to IFX and ADM. Results: Of the patients evaluated, 43.9% had IFX concentrations < 3 mg/l, 17.5% had IFX concentrations > 7 mg/l, and 7% had anti-IFX antibodies. Moreover, 18.5, 52.6, and 28.9% had ADM concentrations < 4 mg/l, 4–8 mg/l, and > 8 mg/l, resp. with 5.2% being positive for anti-ADM antibodies. Patient weight and duration of biological therapy showed statistically significant negative correlations with ADM concentration. Therapy was optimized in 56% of patients by intensification, in 12% by switching, in 8% by swapping, in 8% by adjustment of concomitant therapy, by dose reduction in 4% and by treatment termination in 12%. Clinical remission was achieved in 47.6% of patients and therapeutic responses in an additional 33.3%. Patients who completed treatment remained in remission, whereas de-escalation led to relapse. Concentrations measured by POCT and ELISA methods did not show statistically significant differences, with occasional casuistic clinically significant differences probably due to human error. Conclusion: Reactive pharmacokinetic monitoring has become a regular part of the clinical practice and is widely applied, representing a rational foundation for biological therapy optimization. The future use of proactive monitoring is still open to discussion, dependent in particular on the health care payers’ attitudes.

MeSH
adalimumab farmakokinetika terapeutické užití MeSH
Crohnova nemoc * farmakoterapie MeSH
infliximab farmakokinetika terapeutické užití MeSH
klinická studie jako téma MeSH
lidé MeSH
ulcerózní kolitida * farmakoterapie MeSH
Check Tag
lidé MeSH

Článek

Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis

Arthritis research & therapy. 2020 ; 22 (1) : 60. [pub] 20200326

Arthritis Res Ther
ISSN 1478-6362
Medvik
Zdroj

BACKGROUND: ABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA). METHODS: In this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments. RESULTS: A total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups. CONCLUSIONS: These efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

Článek

Monitorování farmakokinetiky infliximabu u idiopatických střevních zánětů
[Infliximab pharmacokinetics monitoring in inflammatory bowel disease]

Vnitřní lékařství. 2020 ; 66 (8) : e34-e38.

ISSN 0042-773X
Medvik
Zdroj

Terapeutické monitorování koncentrace léčiv představuje strategii pro optimalizaci biologické léčby. Jeho podstatou je měření hladiny léčiva před jeho dalším podáním, kdy je hladina nejnižší, a detekce případných protilátek proti němu. Cílem je zvolit optimální způsob úpravy léčby – intenzifikaci či změnu biologika tak, aby byla pro pacienta bezpečná a zároveň maximálně účinná. Princip optimalizace vychází z podstaty selhání léčby, které může být na podkladě farmakokinetickém nebo farmakodynamickém. V současné době rozlišujeme 2 základní přístupy k monitorování farmakokinetiky. U tzv. reaktivního přístupu měříme hladinu léku a výskyt protilátek ve chvíli, kdy dochází k selhávání terapie, event. došlo k výskytu nežádoucí reakce na podaný lék, u proaktivního přístupu provádíme monitoraci u pacientů v klinické remisi a léčbu optimalizujeme s cílem udržet remisi a zabránit sekundárnímu selhání léčby.

Therapeutic drug monitoring is a strategy utilized to optimize biological therapy. It consists in the drug level measurement before the next dose is due, when the drug concentration reaches the trough level, and includes the detection of potential antidrug antibodies. The monitoring makes it possible to adjust the therapy accordingly – to intensify or change the biologics applied to secure safe and highly effective therapeutics. Therapeutic optimization is based on the nature of therapy failure, which can be caused by pharmacokinetic or pharmacodynamic factors. Pharmacokinetic monitoring can be currently classified as reactive, measuring the drug level and antidrug antibodies during therapy failure, or adverse reactions to the drug applied, and proactive, monitoring patients in clinical remission to retain remission and prevents development of a secondary failure.

MeSH
Crohnova nemoc farmakoterapie MeSH
farmakokinetika MeSH
idiopatické střevní záněty * farmakoterapie MeSH
infliximab aplikace a dávkování farmakokinetika terapeutické užití MeSH
lidé MeSH
monitorování léčiv * metody MeSH
ulcerózní kolitida farmakoterapie MeSH
Check Tag
lidé MeSH
Publikační typ
práce podpořená grantem MeSH
přehledy MeSH

Článek

A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy

Arthritis research & therapy. 2018 ; 20 (1) : 155. [pub] 20180727

Arthritis Res Ther
ISSN 1478-6362
Medvik
Zdroj

BACKGROUND: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%). RESULTS: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

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