Abstract
Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.
Original language | English |
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Pages (from-to) | 400-409 |
Number of pages | 10 |
Journal | CTS-CLINICAL AND TRANSLATIONAL SCIENCE |
Volume | 13 |
Issue number | 2 |
DOIs | |
Publication status | Published - 1 Mar 2020 |
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In: CTS-CLINICAL AND TRANSLATIONAL SCIENCE, Vol. 13, No. 2, 01.03.2020, p. 400-409.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis
T2 - A Prospective Pharmacokinetic-Pharmacodynamic Study
AU - BADBIR Study Group, the BSTOP Study Group, the PSORT Consortium
AU - Pan, Shan
AU - Tsakok, Teresa
AU - Dand, Nick
AU - Lonsdale, Dagan O
AU - Loeff, Floris C
AU - Bloem, Karien
AU - de Vries, Annick
AU - Baudry, David
AU - Duckworth, Michael
AU - Mahil, Satveer
AU - Pushpa-Rajah, Angela
AU - Russell, Alice
AU - Alsharqi, Ali
AU - Becher, Gabrielle
AU - Murphy, Ruth
AU - Wahie, Shyamal
AU - Wright, Andrew
AU - Griffiths, Christopher E M
AU - Reynolds, Nick J
AU - Barker, Jonathan
AU - Warren, Richard B
AU - David Burden, A
AU - Rispens, Theo
AU - Standing, Joseph F
AU - Smith, Catherine H
N1 - Funding Information: C.E.M.G. has received honoraria and/or research grant support (University of Manchester) from AbbVie, Almirall, Bristol Meyers Squibb, Celgene, GSK, Janssen, LEO Foundation, Lilly, Novartis, Pfizer, Sandoz, Sun Pharma, and UCB Pharma. N.J.R. has received honoraria, travel support, and/or research grants (Newcastle University) from AbbVie, Almirall, Celgene, Genentech, Janssen, Novartis, Pfizer, Sanofi Genzyme Regeneron, and UCB Pharma Ltd. J.B. has received honoraria, travel support, and/or research grants (King's College) from AbbVie, Pfizer, Novartis, Janssen, Roche, Regeneron, Lilly, UCB, Sun Pharma, Boehringer Ingelheim, and GSK. R.B.W. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo, Lilly, Novartis, Pfizer, Sanofi, Xenoport, and UCB. A.D.B. has received honoraria from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo, Lilly, Novartis, and Pfizer. T.R. has received honoraria for lectures from Pfizer, AbbVie, and Regeneron, and a research grant from Genmab. D.S. has received departmental research funding from AstraZeneca. C.S. has received departmental research funding from AbbVie, GSK, Pfizer, Novartis, Regeneron, and Roche. N.W. acts as statistician on a trial funded by AstraZeneca. The PSORT consortium has a number of industry partners; see www.psort.org.uk . All other authors declared no competing interests for this work. Funding Information: This work was funded by a Medical Research Council (MRC) Stratified Medicine award (MR/L011808/1). The Psoriasis Association (RG2/10), the NIHR Biomedical Research Centre at King's College London/Guy's and St. Thomas' NHS Foundation Trust, the NIHR Manchester Biomedical Research Centre, and the NIHR Newcastle Biomedical Research Centre. T.T. is supported by an MRC Clinical Research Training Fellowship (MR/R001839/1). N.D. is supported by Health Data Research UK (MR/S003126/1). N.J.R. is supported by the Newcastle MRC/EPSRC Molecular Pathology Node and the Newcastle NIHR Medtech and In vitro diagnostics Co-operative. C.E.M.G. and N.J.R. are NIHR Senior Investigators. J.F.S. is supported by an MRC Fellowship (MR/M008665/1). The authors acknowledge the substantial contribution of Tejus Dasandi, who provided invaluable support with data management; the PSORT, BADBIR, and BSTOP study teams for the delivery of the project, our collaborators within the PSORT consortium (Michael R. Barnes, Paola di Meglio, Richard Emsley, Andrea Evans, and Katherine Payne) and BADBIR study group (Marilyn Benham, Ian Evans, Sagair Hussain, Brian Kirby, Linda Lawson, Kayleigh Mason,?Kathleen McElhone, Anthony Ormerod, and Caroline Owen), The Psoriasis Association for their ongoing support since the inception of BSTOP and PSORT; and the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at King's College London/Guy's and St. Thomas' NHS Foundation Trust, which has provided database infrastructure and support staff. R.B.W. and C.E.M.G. are supported by the Manchester NIHR BRC. The authors also acknowledge the invaluable support of the NIHR through the clinical research networks and its contribution in facilitating recruitment to both BSTOP and BADBIR. Finally, we thank all the patient participants, and acknowledge the enthusiastic collaboration of all of the dermatologists and specialist nurses in the United Kingdom and the Republic of Ireland who recruited to this study (https://bit.do/PIBSTOP). Funding Information: This work was funded by a Medical Research Council (MRC) Stratified Medicine award (MR/L011808/1). The Psoriasis Association (RG2/10), the NIHR Biomedical Research Centre at King's College London/Guy's and St. Thomas' NHS Foundation Trust, the NIHR Manchester Biomedical Research Centre, and the NIHR Newcastle Biomedical Research Centre. T.T. is supported by an MRC Clinical Research Training Fellowship (MR/R001839/1). N.D. is supported by Health Data Research UK (MR/S003126/1). N.J.R. is supported by the Newcastle MRC/EPSRC Molecular Pathology Node and the Newcastle NIHR Medtech and In vitro diagnostics Co‐operative. C.E.M.G. and N.J.R. are NIHR Senior Investigators. J.F.S. is supported by an MRC Fellowship (MR/M008665/1). Publisher Copyright: © 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.
AB - Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.
UR - http://www.scopus.com/inward/record.url?scp=85078663993&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/cts.12725
DO - https://doi.org/10.1111/cts.12725
M3 - Article
C2 - 31995663
SN - 1752-8054
VL - 13
SP - 400
EP - 409
JO - CTS-CLINICAL AND TRANSLATIONAL SCIENCE
JF - CTS-CLINICAL AND TRANSLATIONAL SCIENCE
IS - 2
ER -