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Ustekinumab pharmacokinetics

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https://www.readbyqxmd.com/read/29623442/therapeutic-drug-monitoring-in-pediatric-inflammatory-bowel-disease
#1
REVIEW
Nicholas Carman, David R Mack, Eric I Benchimol
PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS: Drug clearance is affected by a number of patient and disease factors...
April 5, 2018: Current Gastroenterology Reports
https://www.readbyqxmd.com/read/29545207/biological-therapies-in-inflammatory-bowel-disease-beyond-anti-tnf-therapies
#2
Konstantinos H Katsanos, Konstantinos Papamichael, Joseph D Feuerstein, Dimitrios K Christodoulou, Adam S Cheifetz
The pharmacological management of inflammatory bowel disease (IBD) over the last two decades has transitioned from reliance on aminosalycilates, corticosteroids and immunomodulators to earlier treatment with anti-tumor necrosis factor (anti-TNF) therapy. Nevertheless, 20-30% of patients discontinue anti-TNF therapy for primary non-response and another 30-40% for losing response within one year of treatment. These undesirable therapeutic outcomes can be attributed to pharmacokinetic (anti-drug antibodies and/or low drug concentrations) or pharmacodynamic issues characterized by a non-TNF driven inflammation...
March 12, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29420255/development-and-translational-application-of-a-minimal-physiologically-based-pharmacokinetic-model-for-a-monoclonal-antibody-against-interleukin-23-il-23-in-il-23-induced-psoriasis-like-mice
#3
Xi Chen, Xiling Jiang, Rajitha Doddareddy, Brian Geist, Thomas McIntosh, William J Jusko, Honghui Zhou, Weirong Wang
The interleukin (IL)-23/Th 17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model...
April 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29409871/pharmacokinetics-and-exposure-response-relationships-of-ustekinumab-in-patients-with-crohn-s-disease
#4
Omoniyi J Adedokun, Zhenhua Xu, Christopher Gasink, Douglas Jacobstein, Philippe Szapary, Jewel Johanns, Long-Long Gao, Hugh M Davis, Stephen B Hanauer, Brian G Feagan, Subrata Ghosh, William J Sandborn
BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy...
May 2018: Gastroenterology
https://www.readbyqxmd.com/read/29383030/immunogenicity-of-biologics-in-inflammatory-bowel-disease
#5
Séverine Vermeire, Ann Gils, Paola Accossato, Sadiq Lula, Amy Marren
Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD)...
2018: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29370397/primary-non-response-to-tumor-necrosis-factor-antagonists-is-associated-with-inferior-response-to-second-line-biologics-in-patients-with-inflammatory-bowel-diseases-a-systematic-review-and-meta-analysis
#6
Siddharth Singh, John George, Brigid S Boland, Niels Vande Casteele, William J Sandborn
Background and Aims: We sought to analyze whether response to second-line biologic varies depending on reason for discontinuation of primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis. Methods: Through a systematic search through May 31, 2017, we identified 8 randomized controlled trials (RCTs) of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy (PNR vs...
January 23, 2018: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/29022425/biologics-in-pediatric-psoriasis-efficacy-and-safety
#7
Sunil Dogra, Rahul Mahajan
Introduction Childhood psoriasis is a special situation that is a management challenge for the treating dermatologist. As is the situation with traditional systemic agents, which are commonly used in managing severe psoriasis in children, the biologics are being increasingly used in the recalcitrant disease despite limited data on long term safety. Areas covered - We performed an extensive literature search to collect evidence-based data on the use of biologics in pediatric psoriasis. The relevant literature published from 2000 to September 2017 was obtained from PubMed, using the MeSH words 'biologics', 'biologic response modifiers' or 'treatment of pediatric/childhood psoriasis'...
October 12, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28774547/american-gastroenterological-association-institute-technical-review-on-the-role-of-therapeutic-drug-monitoring-in-the-management-of-inflammatory-bowel-diseases
#8
REVIEW
Niels Vande Casteele, Hans Herfarth, Jeffry Katz, Yngve Falck-Ytter, Siddharth Singh
Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease...
September 2017: Gastroenterology
https://www.readbyqxmd.com/read/28632883/importance-of-immunogenicity-testing-for-cost-effective-management-of-psoriasis-patients-treated-with-adalimumab
#9
Fernando Mota, Esmeralda Neves, José Carlos Oliveira, Manuela Selores, Tiago Torres
INTRODUCTION: Up to 30% of patients treated with anti-tumor necrosis factor drugs do not respond adequately, and up to 50% lose response over time. Immunogenicity is now known to be one of the main causes of this loss of response. METHODS: Serum levels of adalimumab and anti-drug antibodies (ADAs) were measured in 19 patients with psoriasis. RESULTS: Eighty-nine percent of the patients were responders (Psoriasis Area Severity Index (PASI) > 75) and 11% were partial responders (PASI 50-75)...
June 2017: Acta Dermatovenerologica Alpina, Panonica, et Adriatica
https://www.readbyqxmd.com/read/28363434/switching-biologics-in-the-treatment-of-psoriatic-arthritis
#10
REVIEW
Joseph F Merola, Benjamin Lockshin, Elinor A Mody
OBJECTIVE: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disorder that requires targeted treatment based on clinical manifestations, symptom severity, comorbidities, and other factors. Moderate or severe peripheral arthritis symptoms are typically treated with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs), and early and aggressive treatment is recommended in order to prevent permanent damage. Although rheumatologists are now able to choose between several bDMARDs for PsA that have different chemical structures, pharmacokinetic properties, dosing regimens, immunogenicity, safety profiles, and mechanisms of action, there is a lack of typical patient profiles or detailed treatment algorithms that can be followed when patients require alterations in their therapeutic regimens...
August 2017: Seminars in Arthritis and Rheumatism
https://www.readbyqxmd.com/read/28352182/role-of-il-17-in-plaque-psoriasis-therapeutic-potential-of-ixekizumab
#11
REVIEW
Tessa L Hanley, Zenas Zn Yiu
Developments in the understanding of the immunopathogenesis of psoriasis have identified interleukin (IL)-17 as the key proinflammatory cytokine in the pathogenesis of plaque psoriasis, with the consequent development of drugs that target this cytokine or associated receptors. Ixekizumab is a subcutaneously administered humanized monoclonal antibody, which acts to neutralize IL-17A. This article reviews the role of IL-17 in the pathogenesis of psoriasis, the biological and pharmacokinetics of ixekizumab and the safety profile and the clinical efficacy of ixekizumab in Phase III clinical trials...
2017: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/28042732/the-potential-utility-of-tildrakizumab-an-interleukin-23-inhibitor-for-the-treatment-of-psoriasis
#12
REVIEW
Zenas Z N Yiu, Richard B Warren
The approved biologic therapies are effective for the treatment of psoriasis, but have limitations. Tildrakizumab has a different mechanism of action and is a humanized immunoglobulin G1κ that binds to the p19 subunit of IL23. Areas covered: Phase I, II and III clinical trials investigated the pharmacokinetics, efficacy, safety and immunogenicity of tildrakizumab for patients with psoriasis. The mean half-life of tildrakizumab is between 20.2 to 28.2 days. Tildrakizumab achieved a PASI 75 of 66% and 74% at week 16 for the doses of 100 mg and 200 mg respectively in a phase IIb randomised clinical trial (RCT), and PASI 75 of 61%/64% and 62%/66% at week 12 for 100 mg and 200 mg respectively in two phase III RCTs...
February 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27956825/ustekinumab-in-treatment-of-crohn-s-disease-design-development-and-potential-place-in-therapy
#13
REVIEW
Parakkal Deepak, Edward V Loftus
Crohn's disease is characterized by a dysregulation of both innate and adaptive immunity responses. Interleukin-12/23 (IL-12/23) pathway has been found to be a major driver of inflammation in adaptive immune responses. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23 and prevents their interaction with their cell surface receptor and further cytokine activation. It is currently approved in the management of plaque psoriasis and psoriatic arthritis...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27610650/target-independent-variable-region-mediated-effects-on-antibody-clearance-can-be-fcrn-independent
#14
Ryan L Kelly, Yao Yu, Tingwan Sun, Isabelle Caffry, Heather Lynaugh, Michael Brown, Tushar Jain, Yingda Xu, K Dane Wittrup
The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of 2 anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences...
October 2016: MAbs
https://www.readbyqxmd.com/read/26488186/the-cost-effectiveness-of-ustekinumab-for-moderate-to-severe-psoriasis
#15
REVIEW
Nicole C Rouse, Michael E Farhangian, Brooke Wehausen, Steven R Feldman
Given its chronicity and impact on quality of life, psoriasis is a costly disease. As new and better treatments are developed, the cost of treating psoriasis has risen. In this drug profile, the authors discuss ustekinumab, its pharmacokinetics, safety profile, and direct and indirect costs to determine its cost-efficacy. The authors searched PubMed with specific search phrases for clinical trials investigating this issue over 5 years. Eleven articles analyzed cost-effectiveness of ustekinumab, and the references of these articles were included...
2015: Expert Review of Pharmacoeconomics & Outcomes Research
https://www.readbyqxmd.com/read/25918417/charge-mediated-influence-of-the-antibody-variable-domain-on-fcrn-dependent-pharmacokinetics
#16
Angela Schoch, Hubert Kettenberger, Olaf Mundigl, Gerhard Winter, Julia Engert, Julia Heinrich, Thomas Emrich
Here, we investigated the influence of the variable fragment (Fv) of IgG antibodies on the binding to the neonatal Fc receptor (FcRn) as well as on FcRn-dependent pharmacokinetics (PK). FcRn plays a key role in IgG homeostasis, and specific manipulation in the crystallizable fragment (Fc) is known to affect FcRn-dependent PK. Although the influence of the antigen-binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism is hitherto only poorly understood. Therefore, we analyzed the two IgG1 antibodies, briakinumab and ustekinumab, that have similar Fc parts but different terminal half-lives in human and systematically engineered variants of them with cross-over exchanges and varied charge distribution...
May 12, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25284845/biologics-in-dermatology-an-integrated-review
#17
REVIEW
Virendra N Sehgal, Deepika Pandhi, Ananta Khurana
The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-α, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed...
September 2014: Indian Journal of Dermatology
https://www.readbyqxmd.com/read/24852042/information-contributed-by-meta-analysis-in-exposure-response-modeling-application-to-phase-2-dose-selection-of-guselkumab-in-patients-with-moderate-to-severe-psoriasis
#18
RANDOMIZED CONTROLLED TRIAL
Chuanpu Hu, Yasmine Wasfi, Yanli Zhuang, Honghui Zhou
Ustekinumab, a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds with high affinity to human interleukin (IL)-12 and IL-23, has been approved to treat patients with psoriasis. Guselkumab is a related human IgG1 monoclonal antibody in clinical development which specifically blocks IL-23. The objective of this study was to study the exposure-response relationship of guselkumab to guide dose selection for a Phase 2 study in patients with moderate-to-severe psoriasis. Data were available from a Phase 1 study of 47 healthy subjects and 24 patients with psoriasis who received various doses of guselkumab...
June 2014: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/24467968/biologic-therapies-in-inflammatory-bowel-disease
#19
REVIEW
Lawrence B Cohen, Radu M Nanau, Faustine Delzor, Manuela G Neuman
Inflammatory bowel disease, including its 2 entities ulcerative colitis and Crohn's disease, is a chronic medical condition characterized by the destructive inflammation of the intestinal tract. Biologics represent a class of therapeutics with immune intervention potential. These agents block the proinflammatory cascade that triggers the activation and proliferation of T lymphocytes at the level of the intestine, therefore reestablishing the balance between the pro- and anti-inflammatory messages. All 7 biologics showing clinical benefits in inflammatory bowel disease are monoclonal antibodies...
June 2014: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/24101949/ustekinumab-in-the-treatment-of-psoriatic-arthritis-latest-findings-and-clinical-potential
#20
Alice Gottlieb, Kirti Narang
Ustekinumab (UST) is a fully human immunoglobulin G1κ (IgG1κ) monoclonal antibody against common sub-unit p40 of interleukin-12 (IL-12) and interleukin-23 (IL-23). IL-12 and IL-23 are essential components of the Th1 and Th17 inflammatory pathways, respectively, and are the key mediators of psoriasis. Psoriatic arthritis (PsA), an important systemic inflammatory disorder, has similar pathogenesis to psoriasis. Many of PsA patients do not respond to tumor necrosis factor (TNF) inhibitor therapy, highlighting the need for additional treatment modalities with distinct mechanisms of action...
October 2013: Therapeutic Advances in Musculoskeletal Disease
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