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Ustekinumab pharmacokinetics

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
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
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
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
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
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
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
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
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
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
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
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
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
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
Reena Khanna, Brian G Feagan
Crohn's disease (CD) results from a pathological immune response to luminal antigens in genetically predisposed individuals. Since the causes of CD are complex and only partially understood, treatment is based on the empiric use of anti-inflammatory drugs. Although multiple therapies for CD currently exist, a substantial proportion of patients are unresponsive to conventional agents. Approximately a third of patients fail treatment with TNF antagonists, and up to 40% of patients who initially benefit subsequently lose response...
August 2013: Immunotherapy
Yaowei Zhu, Qingmin Wang, Bart Frederick, Esther Bouman-Thio, Joseph C Marini, Monica Keen, Kevin J Petty, Hugh M Davis, Honghui Zhou
BACKGROUND AND OBJECTIVE: Ustekinumab, a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody against interleukin-12/23p40, has been reported to be significantly efficacious in treating patients with moderate-to-severe plaque psoriasis. Although the efficacy and safety of ustekinumab have been previously studied in Asian patients with psoriasis, the pharmacokinetics of ustekinumab has not been reported for Asian patients. The objective of this analysis was to compare the pharmacokinetics of ustekinumab in Chinese and non-Chinese subjects...
April 2013: Clinical Drug Investigation
William J Sandborn
There are six important trends that will impact the future of inflammatory bowel disease therapy. (1) Increased use of the biomarkers C-reactive protein (CRP) and fecal calprotectin, and increased imaging with colonoscopy and MRI enterography. (2) Increased use of pharmacokinetics to customize drug dosing for individual patients. Multiple factors impact the pharmacokinetics of monoclonal antibodies including the presence of antidrug antibodies, concomitant immunosuppression and low serum albumin and high CRP concentrations...
2012: Digestive Diseases
Shannon Famenini, Jashin J Wu
Ustekinumab is effective in the treatment of a variety of autoimmune conditions including psoriasis. As a relatively new therapeutic agent, its long-term effects are still under investigation. Short-term studies, however, have revealed ustekinumab to be generally well tolerated and safe. This article provides a comprehensive review of the pharmacokinetics of ustekinumab, its safety profile, adverse effects, and use in pregnancy. The effect of diabetes and prior immunosuppressant therapy is also addressed.
August 2012: Journal of Drugs in Dermatology: JDD
W Sterry, P van de Kerkhof
Psoriasis is a chronic, genetically predisposed skin disorder, characterised by thickened scaly plaques. Although no therapy is recognised as curative, therapies aimed at symptom control include biologic agents that are generally designed to block molecular activation of cellular pathways of a pathogenic immune response. Although biologics are often described as a class, they can be further sub-classified according to properties including structure and molecular target. For example, the two main groups of biologics for the treatment of psoriasis are those targeting cytokines and those targeting T-cells or antigen-presenting cells...
August 2012: Journal of the European Academy of Dermatology and Venereology: JEADV
Chuanpu Hu, Newman Yeilding, Hugh M Davis, Honghui Zhou
Disease status is often measured with bounded outcome scores (BOS) which report a discrete set of values on a finite range. The distribution of BOS data is often non-standard, e.g., J- or U-shaped, thus making standard analysis methods that assume normality inappropriate. Data transformations aiming to achieve normality with BOS can be much more difficult than with many other types of skewed distributions, and application of methodologies explicitly dealing with this problem has not been previously published in pharmacokinetic/pharmacodynamic modeling literature...
August 2011: Journal of Pharmacokinetics and Pharmacodynamics
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