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Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure

Edlund, Helena, PhD*,†; Grisic, Ana-Marija, MPharm*,†; Steenholdt, Casper, MD, PhD, DMSc; Ainsworth, Mark A., MD, PhD, DMSc; Brynskov, Jørn, MD, DMSc; Huisinga, Wilhelm, PhD§; Kloft, Charlotte, PhD*

doi: 10.1097/FTD.0000000000000590
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Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure–response relationship by linking the disease activity markers “Crohn's disease activity index” (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics.

Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure–response relationships. Metrics of exposure included area under the concentration–time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12.

Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other.

Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.

*Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin;

Graduate Research Training Program PharMetrX, Berlin and Potsdam, Germany;

Department of Gastroenterology, Herlev Hospital, Herlev, Denmark; and

§Institute of Mathematics, Universitaet Potsdam, Potsdam, Germany.

Correspondence: Charlotte Kloft, PhD, Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany (e-mail: charlotte.kloft@fu-berlin.de).

H. Edlund and A. -M. Grisic contributed equally to this work.

C. Kloft and W. Huisinga report research grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA, and SANOFI), outside the submitted work. C. Kloft reports research grants from the Innovative Medicines Initiative-Joint Undertaking (DDMoRe), and Diurnal Ltd. H. Edlund is an employee of AstraZeneca. C. Steenholdt reports personal fees from Takeda, Janssen, Abbvie, and Pfizer, outside the submitted work and within the last 36 months. The remaining authors declare no conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received July 11, 2018

Accepted October 15, 2018

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