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adalimumab pharmacokinetics

J-F Colombel, B Jharap, W J Sandborn, B Feagan, L Peyrin-Biroulet, S F Eichner, A M Robinson, N M Mostafa, Q Zhou, R B Thakkar
BACKGROUND: Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). AIM: To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/adalimumab therapy, compared with adalimumab monotherapy in patients with inadequate disease control on conventional therapy...
January 2017: Alimentary Pharmacology & Therapeutics
Christopher Wynne, Mario Altendorfer, Ivo Sonderegger, Lien Gheyle, Rod Ellis-Pegler, Susanne Buschke, Benjamin Lang, Deepak Assudani, Sandeep Athalye, Niklas Czeloth
Background This Phase I study (VOLTAIRE™-PK) aimed to evaluate three-way pharmacokinetic similarity (bioequivalence), safety and immunogenicity of BI 695501 (a Humira® [adalimumab] biosimilar candidate) compared with US- and EU-approved Humira in healthy male subjects. Methods Subjects (N = 327) were randomized 1:1:1 to receive one 40 mg subcutaneous dose of BI 695501, US- or EU-approved Humira; safety was assessed for 70 days. Bioequivalence was evaluated using the average bioequivalence method to test if the 90% confidence intervals (CIs) of the geometric means (BI 695501 versus US- and EU-approved Humira) for the primary endpoints were within pre-specified acceptance ranges (80-125%)...
November 4, 2016: Expert Opinion on Investigational Drugs
Roger A Levy, Renato Guzman, Gilberto Castañeda-Hernández, Manuel Martinez-Vazquez, Guilherme Damian, Carlos Cara
Biologics are increasingly being used to modify the course of immune-mediated inflammatory diseases. Some main agents are monoclonal antibodies and a fusion-protein that target TNF. This group includes adalimumab, infliximab, certolizumab pegol, golimumab and etanercept. Although the efficacy of anti-TNFs is supported by numerous randomized clinical trials, their pharmacokinetics depend on many factors, in particular immunogenicity, which can cause marked and rapid clearance and a consequent decrease in efficacy...
October 14, 2016: Immunotherapy
Maria Myzithras, Tammy Bigwarfe, Hua Li, Erica Waltz, Jennifer Ahlberg, Craig Giragossian, Simon Roberts
Prior to clinical studies, the pharmacokinetics (PK) of antibody-based therapeutics are characterized in preclinical species; however, those species can elicit immunogenic responses that can lead to an inaccurate estimation of PK parameters. Immunodeficient (SCID) transgenic hFcRn and C57BL/6 mice were used to characterize the PK of three antibodies that were previously shown to be immunogenic in mice and cynomolgus monkeys. Four mouse strains, Tg32 hFcRn SCID, Tg32 hFcRn, SCID and C57BL/6, were administered adalimumab (Humira®), mAbX and mAbX-YTE at 1 mg/kg, and in SCID strains there was no incidence of immunogenicity...
September 6, 2016: MAbs
N M Mostafa, A M Nader, P Noertersheuser, M Okun, W M Awni
BACKGROUND: Adalimumab is a tumour necrosis factor-alpha antibody approved for treatment of moderate to severe chronic plaque psoriasis. OBJECTIVE: To characterise population pharmacokinetics of adalimumab 40 mg every other week dosing regimen and impact of immunogenicity on pharmacokinetics, efficacy and safety in psoriasis patients. METHODS: Patients were enrolled in a Phase 3 study comprising a 16-week double-blind, placebo-controlled period, a 17-week open-label period for Week 16 Psoriasis Area and Severity Index (PASI) 75 responders, and a 19-week double-blind, placebo-controlled period for Week 33 PASI 75 responders...
August 22, 2016: Journal of the European Academy of Dermatology and Venereology: JEADV
Christos C Zouboulis
INTRODUCTION: Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 persons-years and a varying prevalence of 0.05-1% have been reported worldwide. AREAS COVERED: This manuscript summarizes the current evidence on chemistry, pharmacodynamics, pharmacokinetics, as well as clinical efficacy, safety and tolerability of the currently approved biologic drug adalimumab in the treatment of active moderate to severe HS in adults...
October 2016: Expert Review of Clinical Immunology
Takashi K Kishimoto, Joseph D Ferrari, Robert A LaMothe, Pallavi N Kolte, Aaron P Griset, Conlin O'Neil, Victor Chan, Erica Browning, Aditi Chalishazar, William Kuhlman, Fen-Ni Fu, Nelly Viseux, David H Altreuter, Lloyd Johnston, Roberto A Maldonado
The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions...
October 2016: Nature Nanotechnology
Primal Kaur, Vincent Chow, Nan Zhang, Michael Moxness, Arunan Kaliyaperumal, Richard Markus
OBJECTIVE: To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. METHODS: Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax)...
July 27, 2016: Annals of the Rheumatic Diseases
Nicola Ferri, Stefano Bellosta, Ludovico Baldessin, Donatella Boccia, Giorgi Racagni, Alberto Corsini
The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs)...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Gurjit S Kaeley, Amy M Evangelisto, Midori J Nishio, Sandra L Goss, Shufang Liu, Jasmina Kalabic, Hartmut Kupper
OBJECTIVE: To examine the clinical and ultrasonographic (US) outcomes of reducing methotrexate (MTX) dosage upon initiating adalimumab (ADA) in MTX-inadequate responders with moderately to severely active rheumatoid arthritis (RA). METHODS: MUSICA (NCT01185288) was a double-blind, randomized, parallel-arm study of 309 patients with RA receiving MTX ≥ 15 mg/week for ≥ 12 weeks before screening. Patients were randomized to high dosage (20 mg/week) or low dosage (7...
August 2016: Journal of Rheumatology
Elizabeth Hyland, Tim Mant, Pantelis Vlachos, Neil Attkins, Martin Ullmann, Sanjeev Roy, Volker Wagner
AIMS: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira(®) (AbbVie), sourced from both the US (US reference product [US-RP]) and Europe (European reference medicinal product [EU-RMP]). METHODS: In this phase 1 double-blind, parallel group trial (EMR200588-001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US-RP or EU-RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate...
October 2016: British Journal of Clinical Pharmacology
María Chaparro, Javier P Gisbert
INTRODUCTION: Medical therapy is the cornerstone of the management of ulcerative colitis (UC) and the goal of the treatment is the induction and maintenance of remission. AREAS COVERED: Mesalamine is the first line treatment in patients with mild to moderate UC. Despite having different formulations available, clinically significant differences in pharmacokinetics and exposure to these drugs have not been observed. Evidence supporting the efficacy of azathioprine and mercaptopurine for maintaining remission is UC patients come from both observational cohorts and clinical trials...
July 2016: Expert Opinion on Pharmacotherapy
Kai-Chun Wu, Zhi Hua Ran, Xiang Gao, Minhu Chen, Jie Zhong, Jian-Qiu Sheng, Michael A Kamm, Simon Travis, Kori Wallace, Nael M Mostafa, Marisa Shapiro, Yao Li, Roopal B Thakkar, Anne M Robinson
BACKGROUND/AIMS: This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). METHODS: Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220-450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8-26; patients received 40 mg adalimumab every other week...
April 2016: Intestinal Research
Nitin Mehrotra, Atul Bhattaram, Justin C Earp, Jeffry Florian, Kevin Krudys, Jee Eun Lee, Joo Yeon Lee, Jiang Liu, Yeruk Mulugeta, Jingyu Yu, Ping Zhao, Vikram Sinha
Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted...
July 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xavier Roblin, Nicolas Williet, Laurent Peyrin-Biroulet
6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i...
June 2016: Inflammatory Bowel Diseases
David Ternant, Christophe Arnoult, Martine Pugnière, Christine Dhommée, Daniel Drocourt, Eric Perouzel, Christophe Passot, Nadine Baroukh, Denis Mulleman, Gérard Tiraby, Hervé Watier, Gilles Paintaud, Valérie Gouilleux-Gruart
Because IgG1 allotypes might have different half-lives, their influence on infliximab (G1m17,1 allotype) pharmacokinetics was investigated in a group of spondyloarthritis patients. Infliximab was found to have a shorter half-life in patients homozygous for the G1m17,1 allotypes than in those carrying the G1m3 with no G1m1 (G1m3,-1) allotype. Because the neonatal FcR (FcRn) is involved in the pharmacokinetics of mAbs, the interaction of different IgG1 allotypes with FcRn was examined using cellular assays and surface plasmon resonance...
January 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Shomron Ben-Horin, Ren Mao, Minhu Chen
BACKGROUND: The advent of biologic agents for the treatment of inflammatory bowel disease (IBD) was accompanied in parallel with emerging understanding of persisting underlying inflammation and ensuing bowel damage that can occur even in patients with seeming clinical remission. This lead to the concepts of mucosal healing and deep remission gaining acceptance as the more desired goals for therapy within an ambitious disease-control therapeutic approach, namely, treat-to-target strategy...
2015: BMC Gastroenterology
Matthieu Piccand, Juliana Bessa, Eginhard Schick, Claudia Senn, Carole Bourquin, Wolfgang F Richter
The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age...
March 2016: AAPS Journal
Diane R Mould
Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. methotrexate). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK...
September 14, 2015: Digestive Diseases
K Papamichael, T Van Stappen, V Jairath, K Gecse, R Khanna, G D'Haens, S Vermeire, A Gils, B G Feagan, B G Levesque, N Vande Casteele
BACKGROUND: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD. AIM: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD...
November 2015: Alimentary Pharmacology & Therapeutics
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