TY - JOUR A1 - Grisic, Ana-Marija A1 - Eser, Alexander A1 - Huisinga, Wilhelm A1 - Reinisch, Walter A1 - Kloft, Charlotte T1 - Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management JF - British journal of clinical pharmacology N2 - 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.
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.
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.
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. KW - C‐ reactive protein remission KW - inflammatory bowel disease KW - infliximab dosing Y1 - 2020 U6 - https://doi.org/10.1111/bcp.14648 SN - 0306-5251 SN - 1365-2125 VL - 87 IS - 5 SP - 2374 EP - 2384 PB - Wiley CY - Hoboken ER - TY - CHAP A1 - Démaris, Alise A1 - Grišić, Ana-Marija A1 - Huisinga, Wilhelm A1 - Walter, Reinisch A1 - Kloft, Charlotte T1 - Evaluation of dosing strategies of anti-TNF alpha monoclonal antibodies using pharmacokinetic modelling and simulation T2 - Journal of Crohn's and Colitis N2 - Background: Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods: A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results: For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion: By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). KW - linical databases KW - crohn's disease KW - regimen KW - monoclonal antibodies KW - body surface area KW - infliximab KW - fat-free mass KW - certolizumab pegol KW - body mass index procedure Y1 - 2020 U6 - https://doi.org/10.1093/ecco-jcc/jjz203.201 SN - 1873-9946 SN - 1876-4479 VL - 14 IS - Supp. 1 SP - S171 EP - S172 PB - Oxford Univ. Press CY - Oxford ER -