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P485 Dosing infliximab in Crohn's disease: Is adjustment for body size justified?

Grisic A.-M.*1,2, Huisinga W.3, Reinisch W.4, Kloft C.1

1Freie Universitaet Berlin, Department of Clinical Pharmacy and Biochemistry, Berlin, Germany 2Graduate Research Training Program PharMetrX, Berlin, Germany 3Universitaet Potsdam, Institute of Mathematics, Potsdam, Germany 4Medical University of Vienna, Department for Gastroenterology and Hepatology, Vienna, Austria

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.

Table 1

Conclusion

By using a simulation approach different dosing regimens of IFX revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment, independent upon dosing regimen. The variability of AUC and Cmax was lowest with BSA-based and BW-based dosing, respectively. According to the results of the study, and taking into account simplicity and pharmacoeconomic reasons the fixed dosing of IFX could be a better alternative to currently recommended BW-based dosing, especially for lighter patients, with 33% more patients benefiting.

References:

[1] DD Wang et al, (2009), Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials, J Clin Pharmacol.

[2] M Dubinsky et al, (2015), Using a pharmacokinetic dashboard to forecast infliximab levels and predict individualized dosing regimens in IBD patients, Gastroenterol.

[3] AA Fasanmade et al, (2011), Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials, Clin Ther.

[4] W Reinisch et al, (2015), Factors associated with short- and long-term outcomes of therapy for Crohn's disease, Clin Gastroenterol Hepatol.