DOP061. Pharmacokinetic considerations for optimising dosing regimens of infliximab in patients with Crohn's disease
H. Andersson1,2, A. Keunecke1, A. Eser3, W. Huisinga4, W. Reinisch3, C. Kloft1, 1Freie Universitaet Berlin, Dept. Clinical Pharmacy and Biochemistry, Berlin, Germany, 2Graduate Research Training Program PharMetrX, Freie Universitaet Berlin, Berlin, Germany, 3Medical University of Vienna, Dept. for Gastroenterology and Hepatology, Vienna, Austria, 4Universitaet Potsdam, Institute of Mathematics, Potsdam, Germany
A substantial proportion of patients with Crohn's disease (CD) lose response to infliximab. Loss of response may be a result of sub-therapeutic concentrations and is, hence, often handled by dose intensification. There is currently no guideline describing how to adjust the dosing regimen when dose intensification is proposed. Patients with higher clearance (CL) will have lower infliximab concentrations. Therefore, a simulation study was designed based on a previously published pharmacokinetic (PK) model , to assess the effect of different dosing adjustments in a subgroup with higher CL.
Concentration-time profiles were simulated in NONMEM 7.2 using a PK model and demographic properties representative of a CD population. New dosing regimens were simulated for a subgroup with higher CL in order to optimise the exposure with respect to a reference group. Dosing regimens with an increase of dose or a decrease of dosing interval were investigated. The regimens were compared with respect to area under the concentration-time curve (AUC), maximal concentration (Cmax), and minimal concentration (Cmin).
Two subpopulations were generated based on serum albumin concentration (sALB) at baseline: low (<35 g/L) and physiological (35–55 g/L, reference group) sALB. Several optimised dosing regimen for the group with low sALB were possible depending on which PK parameter was evaluated. AUC and Cmax were highly influenced by an increase of IFX dose; even a small dose increase resulted in a large increase (see table). Decreasing the dosing interval modestly, yet sufficiently, changed the AUC and Cmin without affecting Cmax. When recognising AUC, Cmax, and Cmin together, the optimal regimen was 5 mg/kg every fifth week (q5w).
|Subpopulation||Dosing regimen||Cmax (mg/L), IQR||Cmin (mg/L), IQR||AUC24w (g*h/L), IQR|
|Physiological sALB||5 mg/kg, q8w||77.1–121||0.637–4.17||55.6–94.7|
|Low sALB||5 mg/kg, q8w||74.9–117||0.139–1.54||38.9–65.3|
|Low sALB||7.5 mg/kg, q8w||114–176||0.225–2.26||57.5–97.1|
|Low sALB||12.5 mg/kg, q8w||188–290||0.360–3.43||94.4–162|
|Low sALB||5 mg/kg, q6w||76.6–120||0.513–3.08||51.7–83.7|
|Low sALB||5 mg/kg, q5w||76.4–117||1.05–5.27||64.1–106|
|qXw, every Xth week; IQR, interquartile range; AUC24w, AUC over 24 weeks.|
This study optimised the dosing regimen for a patient subgroup with higher CL compared with a reference group. Evaluating different PK parameters separately resulted in different recommendations for dose adjustments. Considering all PK parameters together, and the potential risk of adverse events with too high exposure enabled a conclusion: it shall be preferred to shorten the dosing interval compared to increase the amount of drug when a higher CL is the cause of sub-therapeutic concentrations. Further studies are needed to evaluate the PK-pharmacodynamic relationship of infliximab.
1. 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