Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Abstract

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

“…The difference in steady-state dissociation constant (K SS ) estimates between central (15.4 nM) and peripheral (0.49 nM) compartments may be linked to target turnover and expression as well as to differences in infliximab-TNF affinities between central and peripheral compartment. In the central compartment, our K SS estimate is similar to that reported by Berends et al (14 nM [17]), while that of the peripheral compartment is similar to values linked to slow kinetics of complexes reported in previous publications on IBD patients from Kimura et al (0.468 nM, [20]) and us (0.45 nM [11]). Of note, these latter values were dissociation constants (K D ), but they should be similar to K SS values because they were associated with low values of k int [26,35].…”

“…The value of central k int is in agreement with median value reported for mAbs studied using TMDD modeling (0.13 day −1 [16]) but still inferior to the value estimated by Berends et al (0.98 day −1 [17]). Indeed, this latter study quantified a rapid elimination of complexes due to blood circulating TNF-α, while the present, as well as previous ones [11,[18][19][20], may have quantified a slower kinetics of complexes involving the whole antigen mass.…”

“…Up to date, infliximab pharmacokinetics was studied using compartmental modeling in 36 publications, including 22 that used population two-compartment models, of which 15 in IBD patients [32,33]. The influence of target antigen on infliximab pharmacokinetics was suggested in several publications using covariates related to inflammation (CRP levels, fecal calprotectin, erythrocyte sedimentation rate) [16,32], and described using TMDD models in six studies, of which four were made on aggregated data [18][19][20]34], with two using population modeling [11,17].…”

“…The joint kinetics of both infliximab and target may be described using target-mediated drug disposition (TMDD) models [15,16]. Up to date, five publications reported targetmediated pharmacokinetics of infliximab in IBD [11,[17][18][19][20]. However, none of them allowed the description of the interactions of infliximab and TNF-α in the deep compartment.…”

“…However, none of them allowed the description of the interactions of infliximab and TNF-α in the deep compartment. Indeed, four of these studies used one-compartment pharmacokinetic models [11,[18][19][20], while one used a two-compartment TMDD model which described interactions between infliximab and circulating TNF-α levels in the central compartment [17].…”