49 (S0652). - Real World Exposure-Response Relationship of Vedolizumab in Inflammatory Bowel Disease: A Pooled Multicenter Observational Cohort Analysis of Clinical and Modeled Pharmacological Data
Niels Vande Casteele, PharmD, PhD1, William J. Sandborn, MD, FACG1, Brian G. Feagan, MD2, Séverine Vermeire, MD, PhD3, Parambir S. Dulai, MD1, Julian Panés4, Andres Yarur, MD5, Xavier Roblin, MD, PhD6, Shomron Ben-Horin, MD7, Iris Dotan, MD8, Mark Osterman, MD, MSCE9, Dirk Lindner, MSc10, Christian Agboton, MD10, Maria Rosario, PharmD, MSc, PhD11, Teresa Osborn, BS, PharmD12; 1University of California San Diego, La Jolla, CA; 2Robarts Clinical Trials Inc. / Academic Medical Center, Amsterdam, the Netherlands / Western University, London, ON, Canada; 3University Hospitals Leuven, Leuven, Vlaams-Brabant, Belgium; 4Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Catalonia, Spain; 5Medical College of Wisconsin, Milwaukee, WI; 6Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, Auvergne, France; 7Sheba Medical Center, Tel HaShomer, Tel-Aviv University, Ramat Gan, Tel Aviv, Israel; 8Rabin Medical Center, Petah-Tikva, Tel Aviv, Israel; 9University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 10Takeda, Zurich, Zurich, Switzerland; 11Takeda, Cambridge, MA; 12Takeda, Chicago, IL
Introduction: The role of vedolizumab (VDZ) therapeutic drug monitoring in patients with ulcerative colitis (UC) or Crohn’s disease (CD) is under investigation. However, a thorough understanding of the relationship between VDZ serum concentrations and clinical outcomes is lacking. Methods: ERELATE was a retrospective cohort study conducted at 9 centers in 6 countries. Data were pooled from real-world clinical cohorts of patients with UC or CD treated with VDZ. Clinically important treatment outcomes based on definitions commonly used across centers were collected at Weeks 14, 26, and 52. Using a population pharmacokinetic model,1 VDZ dosing, baseline body weight, and albumin concentration were used to predict VDZ concentrations. A Bayesian approach incorporated observed VDZ concentrations to refine individual predicted concentrations. Relationships between predicted concentrations and observed clinically important outcomes were investigated. VDZ concentration thresholds were determined using the optimal Youden index point along the receiver operating characteristic curve. Correlation and agreement between observed and predicted concentrations were evaluated using Spearman (ρ) and intra-class correlation (ICC) coefficients, respectively. Results: In total 695 patients (304 UC, 391 CD) were included; 47.9% were male. Median age was 39 years, median disease duration was 9 years, and 86.3% had prior anti-tumor necrosis factor exposure. Clinically important outcome rates for UC and CD are shown in Table 1. Significant correlation ([ρ=0.879; p< 0.01] across all timepoints) and agreement (ICC=0.722; p< 0.01) were noted between observed and predicted concentrations, indicating adequate Bayesian model prediction of individual VDZ concentrations. Observed exposure-response relationships were more pronounced in UC than CD. Differences in VDZ concentration and drug concentration area under the curve from Weeks 0-6 were observed between remitters and non-remitters for UC and CD combined (Table 2). Predicted VDZ concentrations of 30.8 and 33.8 µg/mL at Week 6 and 16.6 and 14.4 µg/mL at Week 14 were associated with clinical remission and deep remission, respectively, at Week 52. Discussion: These real-world data confirm GEMINI trial findings of significant relationships between VDZ serum concentration and clinical outcomes. Adequate drug concentrations during induction therapy may be important predictors of short- and long-term treatment outcomes. Reference 1. Rosario M, et al.Aliment Pharmacol Ther. 2015;42:188-202.
Table 1. Clinically Important Outcomes in Patients With UC or CD
Table 2. Predicted Vedolizumab Trough Concentrations Associated With Clinical and Deep Remission in Patients With UC or CD
Disclosures: Niels Vande Casteele: Celltrion – Other Financial or Material Support, Personal fees. Prometheus – Other Financial or Material Support, Personal fees. R-Biopharm – Other Financial or Material Support, Research grants. Takeda – Other Financial or Material Support, Grants and personal fees. UCB – Other Financial or Material Support, Grants and personal fees. William Sandborn: AbbVie – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, consulting fees. Allergan – Consultant, Other Financial or Material Support, Consulting Fees. Amgen – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, consulting fees. Arena Pharmaceuticals – Consultant, Other Financial or Material Support, Consulting Fees. Atlantic Healthcare Limited – Grant/Research Support, Other Financial or Material Support, Financial support for research. Avexegen Therapeutics – Consultant, Other Financial or Material Support, Consulting Fees. BeiGene – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Boehringer Ingelheim – Consultant, Other Financial or Material Support, Consulting Fees. Celgene – Consultant, Other Financial or Material Support, Consulting Fees. Celgene/Receptos – Grant/Research Support, Other Financial or Material Support, Financial support for research. Celltrion – Consultant, Other Financial or Material Support, Consulting Fees. Conatus – Consultant, Other Financial or Material Support, Consulting Fees. Cosmo – Consultant, Other Financial or Material Support, Consulting Fees. Escalier Biosciences – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Escalier Biosciences – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds), employee, stock options. Ferring – Consultant, Other Financial or Material Support, Consulting Fees. Forbion – Consultant, Other Financial or Material Support, Consulting Fees. Genentech – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, Consultancy. Gilead Sciences – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, Consultancy. Gossamer Bio – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consultancy. Incyte – Consultant, Other Financial or Material Support, Consulting Fees. Janssen – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, consultancy. Kyowa Kirin Pharmaceutical Research – Consultant, Other Financial or Material Support, Consulting Fees. Landos Biopharma – Consultant, Other Financial or Material Support, Consulting Fees. Lilly – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, Consultancy. Oppilan Pharma – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, consultancy. Oppilan Pharma – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, employee, stock options. Opthotech – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, consultant, stock options. Otsuka – Consultant, Other Financial or Material Support, Consulting Fees. Pfizer – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, Consultancy. Progenity – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, consultant, stock. Progenity – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories) – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, employee, stock options. Prometheus Laboratories (now Prometheus Biosciences) – Consultant, Grant/Research Support, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Financial support for research, stock or stock options, consultancy. Reistone – Consultant, Other Financial or Material Support, Consulting Fees. Ritter Pharmaceuticals – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Robarts Clinical Trials (owned by Health Academic Research Trust, HART) – Consultant, Other Financial or Material Support, Consulting Fees. Series Therapeutics – Consultant, Other Financial or Material Support, Consulting Fees. Shire – Consultant, Other Financial or Material Support, Consulting Fees. Sienna Biopharmaceuticals – Other Financial or Material Support, Consulting Fees. Sigmoid Biotechnologies – Consultant, Other Financial or Material Support, Consulting Fees. Sterna Biologicals – Consultant, Other Financial or Material Support, Consulting Fees. Sublimity Therapeutics – Consultant, Other Financial or Material Support, Consulting Fees. Takeda – Consultant, Grant/Research Support, Other Financial or Material Support, Financial support for research, consulting fees. Theravance Biopharma – Consultant, Other Financial or Material Support, Consulting Fees. TiGenix – Consultant, Other Financial or Material Support, Consulting Fees. Tillotts Pharma – Consultant, Other Financial or Material Support, Consulting Fees. UCB Pharma – Consultant, Other Financial or Material Support, Consulting Fees. Ventyx Biosciences – Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Ventyx Biosciences – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, employee, stock options. Vimalan Biosciences – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, employee, stock options. Vimalan Biosciences – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds), Other Financial or Material Support, Stock or stock options, Consulting Fees. Vivelix Pharmaceuticals – Consultant, Other Financial or Material Support, Consulting Fees. Brian Feagan: Abbott/AbbVie – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. ActoGeniX, – Consultant, Consultancy. Akros – Consultant, Other Financial or Material Support, Consultancy. Albireo Pharma – Consultant, Consultancy. Amgen – Consultant, Grant/Research Support, Grant/research support, consultancy. AstraZeneca – Consultant, Grant/Research Support, Other Financial or Material Support, Consultancy, Grant/Research support. Avaxia Biologics Inc – Consultant, Consultancy. Avir Pharma – Consultant, Consultancy. Axcan – Consultant, Other Financial or Material Support, Consultancy. Baxter Healthcare Corp – Consultant, Other Financial or Material Support, Consultancy. Biogen Idec – Consultant, Consultancy. Boehringer-Ingelheim – Consultant, Consultancy. Bristol-Myers Squibb (BMS) – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. Calypso Biotech – Consultant, Consultancy. Celgene – Consultant, Other Financial or Material Support, Consultancy. Elan/Biogen – Consultant, Other Financial or Material Support, Consultancy. enGene – Consultant, Other Financial or Material Support, Consultancy. Ferring Pharma – Consultant, Other Financial or Material Support, Consultancy. gICare Pharma – Consultant, Other Financial or Material Support, Consultancy. Gilead – Consultant, Consultancy. Given Imaging Inc. – Consultant, Other Financial or Material Support, Consultancy. GSK – Consultant, Other Financial or Material Support, Consultancy. Ironwood Pharma – Consultant, Consultancy. Janssen Biotech (Centocor) – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. Johnson & Johnson/Janssen – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. Kyowa Hakko Kirin Co Ltd – Consultant, Consultancy. Lexicon – Consultant, Consultancy. Lilly – Consultant, Other Financial or Material Support, Consultancy. Lycera BioTech – Consultant, Consultancy. Merck – Consultant, Consultancy. Mesoblast Pharma – Consultant, Other Financial or Material Support, Consultancy. Nektar – Consultant, Other Financial or Material Support, Consultancy. Nestles – Consultant, Other Financial or Material Support, Consultancy. Novartis – Consultant, Other Financial or Material Support, Consultancy. Novo Nordisk – Consultant, Other Financial or Material Support, Consultancy. Pfizer – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. Prometheus Therapeutics and Diagnostics – Consultant, Other Financial or Material Support, Consultancy. Protagonist – Consultant, Other Financial or Material Support, Consultancy. Receptos – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research Support, Consultancy. Robarts Clinical Trials Inc. – Advisory Committee/Board Member, Other Financial or Material Support, Membership (board of directors). Roche/Genentech – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research support, consultancy. Salix Pharma – Consultant, Other Financial or Material Support, Consultancy. Sanofi – Grant/Research Support, Other Financial or Material Support, Grant/research support. Santarus – Grant/Research Support, Other Financial or Material Support, Grant/research support. Serono – Consultant, Other Financial or Material Support, Consultancy. Shire – Consultant, Other Financial or Material Support, Consultancy. Sigmoid Pharma – Consultant, Other Financial or Material Support, Consultancy. Synergy Pharma Inc. – Consultant, Other Financial or Material Support, Consultancy. Takeda – Consultant, Other Financial or Material Support, Consultancy. Teva Pharma – Consultant, Other Financial or Material Support, Consultancy. TiGenix – Consultant, Other Financial or Material Support, Consultancy. Tillotts – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research Support, Consultancy. UCB Pharma – Consultant, Grant/Research Support, Other Financial or Material Support, Grant/research Support, Consultancy. Vertex Pharma – Consultant, Other Financial or Material Support, Consultancy. VHsquared Ltd – Consultant, Other Financial or Material Support, Consultancy. Warner Chilcott – Consultant, Other Financial or Material Support, Consultancy. Wyeth – Consultant, Other Financial or Material Support, Consultancy. Zealand – Consultant, Other Financial or Material Support, Consultancy. Zyngenia – Consultant, Other Financial or Material Support, Consultancy. Séverine Vermeire: AbbVie – Other Financial or Material Support, Lecture fees, Financial support for research, Consultancy. Abivax – Other Financial or Material Support, Consultancy. Celgene – Other Financial or Material Support, Consultancy. Celltrion – Other Financial or Material Support, Consultancy. Centocor – Other Financial or Material Support, Lecture fees, Consultancy. Ferring – Other Financial or Material Support, Lecture fees, Consultancy. Galapagos – Other Financial or Material Support, Consultancy. Genentech/Roche – Other Financial or Material Support, Lecture fees, Consultancy. Gilead – Other Financial or Material Support, Consultancy. GSK – Other Financial or Material Support, Consultancy. Hospira – Other Financial or Material Support, Lecture fees, Consultancy. Johnson & Johnson – Other Financial or Material Support, Lecture fees, Consultancy, Financial support for research. Merck Sharp & Dohme Corp – Other Financial or Material Support, Lecture fees, Consultancy. Mundipharma – Other Financial or Material Support, Consultancy. Pfizer – Other Financial or Material Support, Lecture fees, Consultancy, Financial support for research. ProDigest – Other Financial or Material Support, Consultancy. Prometheus – Other Financial or Material Support, Consultancy. SecondGenome – Other Financial or Material Support, Consultancy. Takeda – Other Financial or Material Support, Lecture fees, Consultancy, Financial support for research. Tillotts – Other Financial or Material Support, Lecture fees, Consultancy. Parambir Dulai: AbbVie – Other Financial or Material Support, Consultancy, Research support. Bulhmann – Other Financial or Material Support, Research support. Janssen – Other Financial or Material Support, Consultancy, Research support. Pfizer – Other Financial or Material Support, Consultancy. Polymedco – Other Financial or Material Support, Research support. Prometheus – Other Financial or Material Support, Research support. Takeda – Other Financial or Material Support, Consultancy, Research support. Julian Panés: AbbVie – Other Financial or Material Support, Financial support for research, Consultancy, Lecture fee. Arena – Other Financial or Material Support, Consultancy. Boehringer-Ingelheim – Other Financial or Material Support, Consultancy. Celgene – Other Financial or Material Support, Consultancy. Celltrion – Other Financial or Material Support, Consultancy. GSK – Other Financial or Material Support, Consultancy. Immunic – Other Financial or Material Support, Consultancy. Johnson & Johnson – Other Financial or Material Support, Lecture fees. Merck Sharp & Dohme Corp – Other Financial or Material Support, Financial support for research. Nestlé – Other Financial or Material Support, Consultancy. Oppilan – Other Financial or Material Support, Consultancy. Pfizer – Other Financial or Material Support, Financial support for research, lecture fees, consultancy. Progenity – Other Financial or Material Support, Consultancy. Takeda – Other Financial or Material Support, Lecture fees, Consultancy. Theravance – Other Financial or Material Support, Consultancy. TiGenix – Other Financial or Material Support, Consultancy. Andres Yarur: Arena Pharmaceuticals – Other Financial or Material Support, Consultant. Prometheus Bioscience – Other Financial or Material Support, Consultant. Takeda – Other Financial or Material Support, Consultant. Xavier Roblin: AbbVie – Other Financial or Material Support, Time consulting and Advisory Board. Amgen – Other Financial or Material Support, Time consulting and Advisory Board. Biogen – Other Financial or Material Support, Time consulting and Advisory Board. Gilead – Other Financial or Material Support, Time consulting and Advisory Board. Janssen – Other Financial or Material Support, Time consulting and Advisory Board. MSD – Other Financial or Material Support, Time consulting and Advisory Board. Pfizer – Other Financial or Material Support, Time consulting and Advisory Board. Takeda – Other Financial or Material Support, Time consulting and Advisory Board. Theradiag – Other Financial or Material Support, Time consulting and Advisory Board. Shomron Ben-Horin: AbbVie – Advisory Committee/Board Member, Consultant, Consultancy/advisory board, Research support. Celltrion – Advisory Committee/Board Member, Consultant, Consultancy/advisory board, Research support. GSK – Advisory Committee/Board Member, Consultant, Consultancy/advisory board. Janssen – Advisory Committee/Board Member, Consultant, Consultancy/advisory board, Research support. Pfizer – Advisory Committee/Board Member, Consultant, Consultancy/advisory board. Takeda – Advisory Committee/Board Member, Consultant, Consultancy/advisory board, Research support. Iris Dotan: AbbVie – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member, Speaker, Research support. Altman Research – Other Financial or Material Support, Research support. Arena – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Celgene – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Celgene/BMS – Other Financial or Material Support, Speaker. Celltrion – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Speaker, Consultant/advisory board member. DSM – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Falk Pharma – Other Financial or Material Support, Speaker. Ferring – Other Financial or Material Support, Speaker. Genentech – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Speaker, Consultant/advisory board member. Gilead – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Janssen – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Speaker, Consultant/advisory board member. Medtronic/given imaging – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Neopharm – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Nestle – Other Financial or Material Support, Speaker. Pfizer – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Speaker, Research Support, Consultant/advisory board member Consultant/advisory board member Consultant/advisory board member. Rafa Laboratories – Advisory Committee/Board Member, Consultant, Other Financial or Material Support, Consultant/advisory board member. Takeda – Advisory Committee/Board Member, Consultant, Speaker, Consultant/advisory board member. Mark Osterman: AbbVie – Other Financial or Material Support, Consultancy fees. Elan – Other Financial or Material Support, Consultancy fees. Janssen – Other Financial or Material Support, Consultancy fees. Lycera – Other Financial or Material Support, Consultancy fees. Merck – Other Financial or Material Support, Consultancy fees. Pfizer – Other Financial or Material Support, Consultancy fees. Takeda – Other Financial or Material Support, Consultancy fees. UCB – Other Financial or Material Support, Financial support for research, Consultancy fees. Dirk Lindner: Takeda – Other Financial or Material Support, Employee of Takeda; holds Takeda stock or stock options. Christian Agboton: Takeda – Other Financial or Material Support, Employee of Takeda; holds Takeda stock or stock options. Maria Rosario: Takeda – Other Financial or Material Support, Employee of Takeda at the time this research was conducted; has granted patents and pending patent applications relating to the clinical pharmacology of vedolizumab.. Teresa Osborn: Takeda – Other Financial or Material Support, Employee of Takeda; holds Takeda stock or stock options.
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