@misc{GrisicHuisingaReinischetal.2017,
  author    = {Grisic, Ana-Marija and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte},
  title     = {P485 Dosing infliximab in Crohn's disease},
  series = {Journal of Crohn's and Colitis},
  volume    = {11},
  journal   = {Journal of Crohn's and Colitis},
  number    = {1},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1093/ecco-jcc/jjx002.609},
  pages     = {S325 -- S326},
  year      = {2017},
  abstract  = {Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database. Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed. Results: For all dosing strategies the variability of Cmin (CV ≈110\%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.},
  language  = {en}
}
@article{GrisicEserHuisingaetal.2020,
  author    = {Grisic, Ana-Marija and Eser, Alexander and Huisinga, Wilhelm and Reinisch, Walter and Kloft, Charlotte},
  title     = {Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management},
  series = {British journal of clinical pharmacology},
  volume    = {87},
  journal   = {British journal of clinical pharmacology},
  number    = {5},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0306-5251},
  doi       = {10.1111/bcp.14648},
  pages     = {2374 -- 2384},
  year      = {2020},
  abstract  = {Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. <br /> Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. <br /> Results The generated quantitative model showed that IFX has the potential to inhibit up to 72\% (9\% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90\% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43\% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55\% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. <br /> Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.},
  language  = {en}
}
@article{EdlundGrisicSteenholdtetal.2019,
  author    = {Edlund, Helena and Grisic, Ana-Marija and Steenholdt, Casper and Ainsworth, Mark Andrew and Brynskov, Torn and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {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},
  series = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  volume    = {41},
  journal   = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  number    = {2},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0163-4356},
  doi       = {10.1097/FTD.0000000000000590},
  pages     = {235 -- 242},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}