Abstract
Background & Aims: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. Methods: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. Results: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. Conclusions: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.
Original language | English (US) |
---|---|
Pages (from-to) | 2244-2255.e9 |
Journal | Clinical Gastroenterology and Hepatology |
Volume | 18 |
Issue number | 10 |
DOIs | |
State | Published - Sep 2020 |
Keywords
- Inflammatory Bowel Disease
- Serum Concentration
- Therapeutic Drug Monitoring
- Treatment Optimization
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis. / Adedokun, Omoniyi J.; Xu, Zhenhua; Marano, Colleen; O'Brien, Chris; Szapary, Philippe; Zhang, Hongyan; Johanns, Jewel; Leong, Rupert W.; Hisamatsu, Tadakazu; Van Assche, Gert; Danese, Silvio; Abreu, Maria T.; Sands, Bruce E.; Sandborn, William J.
In: Clinical Gastroenterology and Hepatology, Vol. 18, No. 10, 09.2020, p. 2244-2255.e9.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis
AU - Adedokun, Omoniyi J.
AU - Xu, Zhenhua
AU - Marano, Colleen
AU - O'Brien, Chris
AU - Szapary, Philippe
AU - Zhang, Hongyan
AU - Johanns, Jewel
AU - Leong, Rupert W.
AU - Hisamatsu, Tadakazu
AU - Van Assche, Gert
AU - Danese, Silvio
AU - Abreu, Maria T.
AU - Sands, Bruce E.
AU - Sandborn, William J.
N1 - Funding Information: Conflicts of interest The authors disclose the following: Omoniyi J. Adedokun, Zhenhua Xu, Colleen Marano, Chris O’Brien, Philippe Szapary, Hongyan Zhang, and Jewel Johanns are employees of Janssen Research & Development, LLC; Rupert W. Leong has received personal advisory board fees from AbbVie, Aspen, Celgene, Ferring, Gilead, Hospira, Janssen, MSD, Novartis, Pfizer, and Takeda, institutional research fees from the Gastrointestinal Society of Australia, Janssen, National Health and Medical Research Council of Australia, Shire, and Takeda, and personal speaker fees from Emerge Health, Ferring, Shire, and Takeda; Tadakazu Hisamatsu has received personal honoraria from AbbVie GK, Celgene KK, EA Pharma Co, Ltd, Janssen Pharmaceutical KK, JIMRO Co, Ltd, Kyorin Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co, Ltd, Nichi-lko Pharmaceutical Co, Ltd, Pfizer, Inc, Takeda Pharmaceutical Co, Ltd, and commercial research funding from AbbVie GK, Asahi Kasei Medical Co, Ltd, Astellas Pharma, Inc, Daiichi-Sankyo Co, Ltd, EA Pharma Co, Ltd, Pfizer, Inc, JIMRO Co, Ltd, Kyorin Pharmaceutical Co, Ltd, Mochida Pharmaceutical Co, Ltd, Nippon Kayaku Co, Ltd, Takeda Pharmaceutical Co, Ltd, and ZERIA Pharmaceutical Co, Ltd; Gert van Assche has received personal speaker and/or consultancy fees from AbbVie, Ferring, Gilead, Janssen, MSD, Pfizer, Roche, Samsung, and Takeda; Silvio Danese has received personal consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals, Inc, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Inc, and Vifor; Maria T. Abreu has received institutional grant/research support from Eli Lilly Pharmaceuticals, Prometheus Laboratories, Pfizer, and Takeda, personal speaking fees from Cornerstones Health, Inc, Focus Medical Communications, Imedex, Takeda, and Vindico Medical Education, and personal consultant fees from AbbVie Laboratories, Allergan, Amgen, Boehringer Ingelheim Pharmaceuticals, Celgene Corporation, Eli Lilly Pharmaceuticals, Focus Medical Communications, Gilead, Janssen Pharmaceuticals, Landos Biopharma, Nestec Ltd–Switzerland, Pfizer, Prometheus Laboratories, Roche Pharmaceuticals, SERES, Shire Pharmaceuticals, and Takeda; Bruce E. Sands has received grants to his institution, personal fees, and nonfinancial support from Janssen, personal fees from AbbVie, Akros Pharma, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, EnGene, Forward Pharma, Immune Pharmaceuticals, Ironwood Pharmaceuticals, Lycera, Lyndra, Receptos, Shire, Synergy Pharmaceuticals, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, TopiVert Pharma, and Salix, grant, personal fees, and nonfinancial support from Celgene, Janssen, Pfizer, and Takeda, personal fees and nonfinancial support from 4D Pharma, Capella Bioscience, Ferring, Gilead, Hoffman-La Roche, Lilly, MedImmune, Oppilan Pharmaceuticals, Otsuka, Palatin Technologies, Protagonist Therapeutics, Rheos Medicines, Seres Therapeutics, UCB, and Vivelix Pharmaceuticals outside of the submitted work; and William J. Sandborn has received institutional research grants from AbbVie, Amgen, Atlantic Healthcare Limited, Celgene/Receptos, Genentech, Gilead Sciences, Janssen, Lilly, Pfizer, Prometheus Laboratories (now Prometheus Biosciences), and Takeda, personal consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, and Vivelix Pharmaceuticals, and personally owns stock or stock options in BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Funding Information: FundingJanssen Research & Development, LLC, funded the clinical trials, providing data for these analyses. Conflicts of interest The authors disclose the following: Omoniyi J. Adedokun, Zhenhua Xu, Colleen Marano, Chris O'Brien, Philippe Szapary, Hongyan Zhang, and Jewel Johanns are employees of Janssen Research & Development, LLC; Rupert W. Leong has received personal advisory board fees from AbbVie, Aspen, Celgene, Ferring, Gilead, Hospira, Janssen, MSD, Novartis, Pfizer, and Takeda, institutional research fees from the Gastrointestinal Society of Australia, Janssen, National Health and Medical Research Council of Australia, Shire, and Takeda, and personal speaker fees from Emerge Health, Ferring, Shire, and Takeda; Tadakazu Hisamatsu has received personal honoraria from AbbVie GK, Celgene KK, EA Pharma Co, Ltd, Janssen Pharmaceutical KK, JIMRO Co, Ltd, Kyorin Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co, Ltd, Nichi-lko Pharmaceutical Co, Ltd, Pfizer, Inc, Takeda Pharmaceutical Co, Ltd, and commercial research funding from AbbVie GK, Asahi Kasei Medical Co, Ltd, Astellas Pharma, Inc, Daiichi-Sankyo Co, Ltd, EA Pharma Co, Ltd, Pfizer, Inc, JIMRO Co, Ltd, Kyorin Pharmaceutical Co, Ltd, Mochida Pharmaceutical Co, Ltd, Nippon Kayaku Co, Ltd, Takeda Pharmaceutical Co, Ltd, and ZERIA Pharmaceutical Co, Ltd; Gert van Assche has received personal speaker and/or consultancy fees from AbbVie, Ferring, Gilead, Janssen, MSD, Pfizer, Roche, Samsung, and Takeda; Silvio Danese has received personal consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals, Inc, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Inc, and Vifor; Maria T. Abreu has received institutional grant/research support from Eli Lilly Pharmaceuticals, Prometheus Laboratories, Pfizer, and Takeda, personal speaking fees from Cornerstones Health, Inc, Focus Medical Communications, Imedex, Takeda, and Vindico Medical Education, and personal consultant fees from AbbVie Laboratories, Allergan, Amgen, Boehringer Ingelheim Pharmaceuticals, Celgene Corporation, Eli Lilly Pharmaceuticals, Focus Medical Communications, Gilead, Janssen Pharmaceuticals, Landos Biopharma, Nestec Ltd?Switzerland, Pfizer, Prometheus Laboratories, Roche Pharmaceuticals, SERES, Shire Pharmaceuticals, and Takeda; Bruce E. Sands has received grants to his institution, personal fees, and nonfinancial support from Janssen, personal fees from AbbVie, Akros Pharma, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, EnGene, Forward Pharma, Immune Pharmaceuticals, Ironwood Pharmaceuticals, Lycera, Lyndra, Receptos, Shire, Synergy Pharmaceuticals, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, TopiVert Pharma, and Salix, grant, personal fees, and nonfinancial support from Celgene, Janssen, Pfizer, and Takeda, personal fees and nonfinancial support from 4D Pharma, Capella Bioscience, Ferring, Gilead, Hoffman-La Roche, Lilly, MedImmune, Oppilan Pharmaceuticals, Otsuka, Palatin Technologies, Protagonist Therapeutics, Rheos Medicines, Seres Therapeutics, UCB, and Vivelix Pharmaceuticals outside of the submitted work; and William J. Sandborn has received institutional research grants from AbbVie, Amgen, Atlantic Healthcare Limited, Celgene/Receptos, Genentech, Gilead Sciences, Janssen, Lilly, Pfizer, Prometheus Laboratories (now Prometheus Biosciences), and Takeda, personal consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, and Vivelix Pharmaceuticals, and personally owns stock or stock options in BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Publisher Copyright: © 2020 AGA Institute
PY - 2020/9
Y1 - 2020/9
N2 - Background & Aims: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. Methods: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. Results: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. Conclusions: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.
AB - Background & Aims: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. Methods: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. Results: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. Conclusions: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.
KW - Inflammatory Bowel Disease
KW - Serum Concentration
KW - Therapeutic Drug Monitoring
KW - Treatment Optimization
UR - http://www.scopus.com/inward/record.url?scp=85089492541&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089492541&partnerID=8YFLogxK
U2 - 10.1016/j.cgh.2019.11.059
DO - 10.1016/j.cgh.2019.11.059
M3 - Article
C2 - 31816446
AN - SCOPUS:85089492541
VL - 18
SP - 2244-2255.e9
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
SN - 1542-3565
IS - 10
ER -