Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease

External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease

“…Several MIPD approaches have recently shown major success in supporting and optimizing dosing regimen selection for various drugs [ 28 , 59 , 60 , 61 , 62 ]. As infliximab trough concentrations exhibit high inter-individual variability and, hence, contribute to a high rate of primary and secondary non-response [ 9 , 12 , 13 , 14 , 18 ] and as infliximab drug exposure is a predictor of clinical response [ 6 , 10 , 11 , 12 ], dose selection for infliximab could benefit considerably from population pharmacokinetic modeling and MIPD [ 31 , 63 ]. Consequently, many efforts have been made to analyze infliximab PK, quantifying and explaining inter-individual variability in various population pharmacokinetic models [ 21 , 23 , 24 , 25 , 26 , 27 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

“…Infliximab exhibits linear pharmacokinetic behavior, while low trough concentrations are associated with impaired or even loss of response to infliximab therapy [ 6 , 7 , 8 , 9 ]. UC patients with detectable serum infliximab trough concentrations showed a 4 times higher probability and CD patients even a 13 times higher probability of being in clinical remission, making serum infliximab levels a predictor of clinical response [ 6 , 9 , 10 , 11 , 12 ]. According to a recent guideline from the American Gastroenterological Association Institute, infliximab should be dosed to achieve target trough concentrations of ≥ 5 µg/mL in order to improve therapy outcome [ 13 ].…”

“…According to a recent guideline from the American Gastroenterological Association Institute, infliximab should be dosed to achieve target trough concentrations of ≥ 5 µg/mL in order to improve therapy outcome [ 13 ]. However, a high inter-individual variability in infliximab trough levels has been observed contributing to a high rate of treatment failure [ 9 , 12 , 13 , 14 ]. About 10–40% of patients fail to respond to induction therapy (primary non-response) [ 15 ], and subsequently, 13% of patients lose response annually after initially responding (secondary non-response) [ 16 ].…”

“…About 10–40% of patients fail to respond to induction therapy (primary non-response) [ 15 ], and subsequently, 13% of patients lose response annually after initially responding (secondary non-response) [ 16 ]. One of the reasons for primary and secondary non-response is the formation of anti-drug antibodies (ADAs) against infliximab, leading to an increased infliximab clearance (CL) [ 9 , 17 , 18 ].…”

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

“…However, a recent study from our group suggested that antigen mass (i.e., total amount of TNF-α able to interact with infliximab) is more than 200 fold higher than circulating TNF-α and that trough infliximab serum concentrations above target values do not lead to sustained TNF-α inhibition [11]. In IBD, since this phenomenon is not associated with systematic loss of response, and that TNF-α reservoir is admitted to be both circulating and expressed on intestine inflammatory cells (monocytes, macrophages) [12][13][14], it may be hypothesized that infliximab's effect is related to its binding to TNF-α in a 'deep' compartment.…”