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J Crohns Colitis. 2017 Jan;11(1):35-46. doi: 10.1093/ecco-jcc/jjw133. Epub 2016 Jul 20.

Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies.

Author information

1
Department of Global Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, PA, USA OAdedoku@its.jnj.com.
2
Department of Global Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, PA, USA.
3
Department of Clinical Development Immunology, Janssen Research & Development, LLC, Spring House, PA, USA.
4
Department of Translational Medicine Sciences, Janssen Research & Development, LLC, Spring House, PA, USA.
5
Department of Clinical Biostatistics, Janssen Research & Development, LLC, Spring House, PA, USA.
6
Department of Biologics Development Sciences, Janssen Research & Development, LLC, Spring House, PA, USA.
7
Department of Gastroenterology, Universitätsklinik für Innere Medizin III, Vienna, Austria & McMaster University, Hamilton, ON, Canada.
8
Department of Gastroenterology, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
9
Department of Gastroenterology, Hospital Gasthuisberg, Leuven, Belgium.
10
Department of Gastroenterology, University of California San Diego, La Jolla, CA, USA.

Abstract

BACKGROUND AND AIMS:

To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies.

METHODS:

We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses.

RESULTS:

Median SGCs peaked at induction wk2 for golimumab 100/50mg, 200/100mg, and 400/200mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 μg/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8-44 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33-1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher efficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100mg, whereas drug levels were slightly higher with golimumab 50mg with vs without immunomodulators.

CONCLUSIONS:

SGCs are approximately dose proportional, and a positive SGC-efficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies.

KEYWORDS:

Ulcerative colitis; anti-tumour necrosis factor; pharmacokinetics

PMID:
27440869
PMCID:
PMC5175493
DOI:
10.1093/ecco-jcc/jjw133
[Indexed for MEDLINE]
Free PMC Article

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