Pharmacokinetics (pK) describes the effects of the body’s physiological processes on an administered drug. For monoclonal antibodies (IgGs), adequate concentrations of the drug need to be achieved in the circulation for it to obtain its intended effects on circulating and intestinal mucosal cells. Individuals’ differences in bioavailability and pK have been associated in IBD with lack of clinical response and mucosal healing. Intravenous administration of anti-TNFs, such as infliximab, allows for administration of large volumes, rapid central distribution, and low variability in bioavailability; peak serum concentrations are attained almost immediately post-infusion [21]. In contrast, subcutaneous anti-TNFs can only be given in low-volume doses and are taken up by lymphatic drainage and paracellular movement, leading to slower absorption into the vascular compartment. For adalimumab, peak serum concentrations are reached approximately 5 days after a single 40 mg dose, with average bioavailability around 65% [21]. Once in the circulation, extravasation of anti-TNFs occurs primarily via receptor-mediated endocytosis into vascular endothelial cells. The volume of distribution of anti-TNFs is ~0.1 L/kg, suggesting these drugs are mainly distributed within the extracellular fluid [22]. Preliminary data with biosimilar infliximab (CT-P13) and adalimumab (ABP501) also report comparable pK profiles to their reference products in rheumatological diseases [7].

Elimination of monoclonal antibodies occurs mostly via proteolytic catabolism by phagocytic cells of the reticuloendothelial system [23]. The reported serum half-life of infliximab ranges from 7 to 12 days in patients with Crohn’s disease, in both those in remission and those with active disease [24, 25]. There is also the phenomenon of the “antigen sink” whereby internalization of anti-TNFs by their binding to mTNF can lead to their clearance from the extracellular space. This may explain the variability in clearance associated with inflammatory burden in patients with ulcerative colitis [26]. Balancing this process is the recycling of intact monoclonal antibodies back into the circulation, leading to the long serum half-life of IgGs (~23 days) and the slow systemic clearance of about 11–15 mL/h [25]. This system is disrupted by the presence of anti-drug antibodies (ADAs); ADAs congregate anti-TNFs into multimeric antibody complexes that are retained and degraded, but not recycled, by reticuloendothelial cells [27]. As an example of the impact of these ADAs on clearance, the clearance of infliximab increases threefold in patients with ADAs as compared with patients without ADAs [28]. The development of ADAs in patients with IBD is influenced by many factors, including genotype, trough drug levels, and concomitant medications [29]. Finally, fecal loss of anti-TNFs has been described as a particular problem to patients with active IBD. In patients with severe IBD, infliximab was noted in a greater proportion of patients failing therapy, compared to those with a clinical response [30]. It is unclear whether the drug leakage caused the loss of response or whether ongoing mucosal inflammation led to drug leakage.

Much study has been undertaken in recent years on the association between pK and clinical response to anti-TNFs and will be covered in detail in another chapter of this book. For many drugs, response is dependent on drug concentrations or drug exposure (the AUC), and therefore drug concentration-guided individualized therapy can be important [24]. For infliximab, for example, a meta-analysis concluded that patients who achieved an infliximab level >2 μg/mL were more three times more likely to be in clinical remission or achieve endoscopic remission than patients with levels <2 μg/mL [31]. This concentration-effect relationship has also been described for adal imumab, certolizumab, and golimumab [21].

Two anti-integrins are currently FDA approved for use in IBD: natalizumab and vedolizumab. Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. Although approved to treat Crohn’s disease, its association with progressive multifocal leukoencephalopathy (PML) has limited its use in IBD, particularly since the approval of vedolizumab. Vedolizumab is a humanized monoclonal antibody which acts against α4β7 integrin heterodimer and blocks the interaction of α4β7 integrin with MAdCAM-1. Other anti-integrins remain in clinical development, such as etrolizumab and the anti-MAdCAM antibody PF-00547659. Since vedolizumab is the only currently approved and widely used anti-integrin, this section will primarily discuss this agent.

The cytokines IL-12 and IL-23 are secreted heterodimeric cytokines, which both contain a p40 protein subunit. IL-12 is primarily produced by phagocytic and dendritic cells in response to microbial stimulation and drives cell-mediated immunity by inducing lymphokine-activated killer cells and activation of natural killer (NK) cells and T lymphocytes, particularly Th1 populations [43]. IL-23 drives a population of T-cells (Th17) that produce IL-17, IL-6, and TNF [44]. In IBD, genome-wide association studies revealed that variants of the gene encoding the IL-23 receptor, and the p40 chain, conferred genetic risk for developing IBD. IL-17 mRNA expression is increased in the colon of patients with active UC and CD, correlating with the density of CD4+ T-cells [45]. IL-17 production by isolated lamina propria CD4+ T-cells from patients with UC is significantly increased by IL-23 [46]. IL-17 appears to play a role in IBD pathogenesis, as it can stimulate innate immune cells and epithelial cells to produce IL-1, IL-6, and IL-8, which induce increased neutrophil recruitment and other pro-inflammatory signals [47]. However, it should be noted that there is also evidence that IL-17 plays a role in mucosal homeostasis, with protective effects on the intestinal epithelium, and generation of antimicrobial peptides [13].