Brendan Halloran, MD
Volume 2 | Issue 11
Higher biologic serum levels are generally associated with increased efficacy in the treatment of inflammatory bowel disease (IBD).(1) This dose-effect relation is well established for infliximab but less so for adalimumab, although experts suspect a similar dose-effect relation will eventually be shown for adalimumab. The pharmacokinetic profile of infliximab has been derived primarily from large clinical studies in adult patients. In these studies, the half-life for infliximab has been reported to range between 7 and 12 days, with a volume of distribution 4.5 to 6.l L.
Of critical importance to daily clinical care, elimination of infliximab has been found to vary considerably between individuals, and possibly in different clinical conditions. For example, infliximab appears to have considerably increased clearance in patients with severe disease. Males tend to have higher drug clearance than females, likely based on differences in body weight. Clearance is lower in patients with higher albumin levels and with concomitant immunosuppressive therapy. Antidrug antibodies (ADAs) increase clearance and may be the most important factor regulating drug levels.
High ADA titres are also associated with low infliximab trough levels and poor treatment response in pediatric Crohn’s disease.(2) This study, which assessed serum infliximab levels in 133 blood samples from 37 pediatric patients with IBD, also found that young children who had lower body weight had lower infliximab levels during induction, as did patients with substantial inflammation. The relation of these lower levels during induction to therapeutic response is not known, although studies have found that the pharmacokinetics of infliximab appear comparable in adults and children, being related to weight rather than age.
A recently identified and interesting phenomenon is the transience of ADAs to infliximab in some patients. A retrospective study assessed 1,232 consecutive serum samples from 90 patients with IBD.(3) Of these patients, 57 had previously detected antibodies and 33 did not, using a new homogenous mobility shift assay. ADAs disappeared over time in approximately one-quarter of patients in whom they had originally been measured, and the treatment response was restored. Transient ADAs were present at substantially lower concentrations than ADAs that proved to be persistent and that led to persistent loss of response and treatment discontinuation.
The relation between trough serum levels, ADAs, and outcomes has also been investigated for adalimumab in Crohn’s disease.(4) A prospective program followed 168 patients with Crohn’s disease treated with adalimumab, measuring trough levels and ADAs using enzyme-linked immunosorbent assays. Low trough serum concentrations were more common among patients with ADAs, indicating more rapid elimination of adalimumab, and these low trough levels were directly related to treatment discontinuation.
With drug and antibody levels becoming widely available, the coming year will yield additional information about individual pharmacokinetics of biologic agents that will eventually lead to effective personalized dosing.
Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…