Pharmacokinetics

Pharmacokinetics of Anti-TNF Monoclonal Antibodies in Inflammatory Bowel Disease: Adding Value to Current Practice

The Journal of Clinical Pharmacology 2015 55(S3) S39–S50 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.374

Niels Vande Casteele, PharmD, PhD and Ann Gils, PharmD, PhD

Abstract Since anti-tumor necrosis factor (TNF) antibodies were introduced to treat patients with inflammatory bowel diseases, short- and long-term clinical and endoscopic endpoints can be achieved that were unreachable with conventional anti-inflammatory agents. Although a large proportion of patients (70–90%) initially respond to the treatment, remission rates after induction are still low (20–50%) and patients are at risk to lose response to the drug over time. This inter-individual variability in response is likely to be influenced by the observed inter-individual variability in pharmacokinetics. By extensively reviewing the literature, we evaluated the potential role of therapeutic drug monitoring to optimize dosing of anti-TNF drugs. Thereby we emphasize some of the pharmacokinetic cornerstones that can help to understand the observed concentration–effect relationship. After discussing some of the most commonly used assays to measure anti-TNF drug and anti-drug antibody concentrations, we reviewed the application of those tests and their potential clinical value in retrospective and prospective studies.

Keywords adalimumab, certolizumab pegol, Crohn’s, disease, golimumab, immunogenicity, inflammatory bowel disease, infliximab, personalized medicine, therapeutic drug monitoring, trough level, ulcerative colitis

Monoclonal antibodies are used in the treatment of several chronic inflammatory diseases, cardiovascular diseases, and oncology. The advantage of antibodies or antibody derivatives is their specificity for the target antigen and in case of full antibodies, their powerful effector mechanisms.1 A major downside, however, is that the immune system can recognize these biologics as non-self, leading to the development of anti-drug antibodies (ADA). ADA can bind to the drug, thereby neutralizing its activity or causing a faster clearance and ultimately resulting in a loss of function of the drug that can be insurmountable. Especially for chronic inflammatory indications where it is typically required to administer the drug over a long period of time, this might constitute losing a (last) therapeutic option. In combination with the high cost of biologics and the potential risk for drug-related side effects, efforts are made to investigate alternative and more rational dosing strategies. For this review we focused on the anti-inflammatory monoclonal antibodies used in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). For these indications, therapeutic options are limited, especially for those patients who have become refractory to less potent anti-inflammatory agents (azathioprine and methotrexate) or have become corticosteroid-dependent. The majority of monoclonal antibodies currently available for treating CD and UC patients are directed against tumor necrosis factor a (TNF). Their working

mechanism is not completely elucidated, but it is believed that both the neutralization of soluble TNF and transmembrane TNF, as well as its ability to induce apoptosis are important effector mechanisms of anti-TNF treatment.2 A recent paper by Katz et al revealed interleukin 2 inhibition as one of the mechanisms of anti-TNF efficacy in IBD.3 In the United States and Europe, infliximab (Remicade1), a chimeric IgG1 k monoclonal antibody and adalimumab (Humira1), a fully human IgG1 k monoclonal antibody are approved for the

Abbreviations: ADA, anti-drug antibodies; CD, Crohn’s disease; CI, confidence interval; CRP, C-reactive protein; ELISA, enzyme-linked immunosorbent assay; HMSA, homogenous mobility shift assay; IQR, interquartile range; IV, intravenous; PK, pharmacokinetic; RIA, radioimmunoassay; RR, risk ratio; SC, subcutaneous; TDM, therapeutic drug monitoring; TNF, tumor necrosis factor; UC, ulcerative colitis. Department of Pharmaceutical and Pharmacological Sciences, Therapeutic and Diagnostic Antibodies, KU Leuven – University of Leuven, Herestraat, Leuven, Belgium Submitted for publication 28 May 2014; accepted 31 July 2014. Corresponding Author: Niels Vande Casteele, PharmD, PhD, Department of Pharmaceutical and Pharmacological Sciences, Therapeutic and Diagnostic Antibodies, KU Leuven, University of Leuven, Campus Gasthuisberg O&N2, PO 820 Herestraat 49, B-3000 Leuven, Belgium. Email: [email protected]

S40 treatment of moderately to severely active CD and UC.4–8 In the United States and not in Europe, certolizumab pegol (Cimzia1), a pegylated humanized Fab’ fragment is approved for the treatment of moderately to severely active CD.9,10 Furthermore, both in the United States and Europe, golimumab (Simponi1), a fully human IgG1 k monoclonal antibody is approved for the treatment of moderately to severely active UC.11 Monoclonal antibodies that interact with leucocyte trafficking out of the gut have shown promising results for the treatments of IBD, vedolizumab, and natalizumab are currently approved for the treatment of CD in the United States.12,13

Response and Loss of Response to Anti-TNF Monoclonal Antibodies Since anti-TNF agents have been available to treat patients with inflammatory bowel disease, short- and long-term clinical, and endoscopic endpoints can now be achieved that were unreachable with conventional antiinflammatory agents.14 Unfortunately 10–30% patients will not respond to anti-TNF treatment (primary nonresponse) and 30–60% of the patients initially responding will lose clinical benefit during the first year of treatment (secondary loss of response).15,16 Primary Non-response Primary non-response is defined as a lack of clinical response to the treatment, assessed 8–12 weeks after initiation.17 It is believed that primary non-response is mainly driven through mechanistic override of the disease (ie, patients not having a TNF driven disease). However, it was shown that CD patients not responding to one antiTNF can benefit from a switch to another anti-TNF.18,19 Possible explanations could be differences in pharmacokinetic (PK) properties, working mechanism or tissue penetration of the different anti-TNF agents.20–22 Other factors could also play a role in primary non-response such as genetic predisposition or an early immunogenic effect.23 Another hypothesis might be that some patients are “misclassified” because of a high disease burden at start of treatment and a too low induction dose of antiTNF relative to the disease state of the patient.24 Secondary Loss of Response Secondary loss of response is defined as a loss of clinical benefit of anti-TNF treatment [eg, increase of symptoms or C-reactive protein (CRP)] after initially responding. It can either be attributed to disease-related factors or drugrelated factors such as the formation of ADA that neutralize the drug’s activity or cause a faster clearance of the drug. Empirically, at time of secondary loss of response either the interval between infusions/injections is shortened or the dose is increased.25 Despite these dose

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adjustments, the median drop-out rate from anti-TNF treatment was calculated to be 7.1–13% per patient-year of follow-up.17,26 In addition, it was hypothesized that anti-TNF therapy can promote alternative inflammatory pathways (eg, interleukin 17 and interleukin 23 pathway and interferon alpha).27

Pharmacokinetics of Monoclonal Antibodies A drug can only exert its pharmacological effect when adequate concentrations of drug are achieved in the circulation and at the drug’s site of action. Inter- and intraindividual differences in bioavailability and PK may contribute to the problem of insufficient or loss of response. Absorption The route of administration can influence the PK of a drug. Infliximab is administered intravenously (IV), allowing for administration of large volumes and a rapid central distribution with low variability in bioavailability. Typically peak serum concentrations are attained almost immediately post-infusion. Infliximab is administered IV at the hospital or infusion center. Adalimumab, certolizumab pegol, and golimumab are administered subcutaneously (SC) by the patient, and can be preferred by the patient for practical reasons. It is assumed that SC administered antibodies are taken up by lymphatic drainage and paracellular movement. Given that the lymph fluid drains slowly into the vascular system, the absorption may continue for hours.28 SC administration constitutes a few problems, eg, the rather low volume that can be administered (often not more than one milliliter) and the inter-individual variability in bioavailability. For adalimumab peak serum concentrations were reached approximately 5 days after SC administration of a single 40 mg dose to adults with an average bioavailability of 64% as described in the European product assessment report of Humira1. In general, a bioavailability ranging from 50 to 100% was described after SC or IM administration.28 Since only a low volume can be injected, SC drugs need to be highly concentrated (ie, need for good formulation to avoid aggregation) and administered more frequently than IV drugs. Given the abundant presence of dendritic cells in the skin, it is believed that the SC environment is particularly hostile toward immunogenic proteins, making SC administration more likely to elicit an immunogenic response compared to IV administration.29 However, the only comparative data comes from a phase IIIb study in rheumatoid arthritis patients where the subcutaneous administration of the fusion protein abatacept (inhibits the

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co-stimulation of T-cells) was compared to the intravenous delivery of the drug.30 This study showed, in contrast, that a slightly higher percentage of patients developed ADA in the IV group (2.3%) compared to the SC group (1.1%). Distribution Extravasation of antibodies may occur through para- or transcellular movement via convection (ie, movement of antibody together with fluid flow from circulation to tissue), diffusion or receptor-mediated endocytosis.1 Because of their high molecular weight and hydrophilicity, transcellular diffusion is unlikely for antibodies. Receptor-mediated endocytosis may occur via FcgR which are present on a variety of cells or via internalization of the antibody bound to membrane-associated antigen.31 Fluid phase endocytosis is suggested to be an important mechanism for extravasation of antibodies into vascular endothelial cells. Once within the acidic environment of endosomes, the IgG antibody may be bound by FcRn which is mainly expressed by vascular endothelial cells. When bound to FcRn, the IgG antibody is protected from degradation and either released back into the circulation and/or into the interstitial fluid.32 Nevertheless, antibodies are mainly distributed within the extracellular fluid. Antibodies seem to have a volume of distribution of approximately 0.1 l/kg.33 Metabolism and Elimination Due to their large size, renal clearance of antibodies is almost non-existent. For certolizumab pegol, the molecular mass was increased above the glomerular filtration limit (
70 kDa) by PEGylation, thereby prolonging the half-life of the compound. Other advantages of PEGylation include a reduced antigenicity and increased solubility.34 The ways through which antibodies are metabolized and excreted from our body are not entirely known, but it constitutes interplay of different mechanisms. Proteolytic catabolism by phagocytic cells of the immune system (reticuloendothelial system): the antibody binds to the FcgR after which it is internalized and degraded.31 There could be an inter-individual variability in clearance via FcgR owing to different polymorphisms of the receptors.35–37 Internalization and degradation in lysosomes by binding of the antibody to membrane-associated antigens (eg, membrane-bound TNF in the case of anti-TNF).31 Not only is this pathway important for the distribution of the antibody; dependent on the cellular antigen and the activation of the downstream cascade upon antibodyantigen binding, this can influence the antibody’s clearance (ie, “antigen sink”).28 It was shown for example that infliximab is able to bind to peripheral blood lymphocytes and lamina propria T cells and subsequently induce apoptosis of activated lymphocytes.22 Further-

S41 more, an inverse correlation between the acute phase reactant CRP and anti-TNF antibody PK was observed in CD and UC patients treated with infliximab.38,39 These catabolic routes are countered by recycling of IgG back into the circulation and/or interstitial fluid through FcRn, explaining the long half-lives of IgG. The serum half-life of IgG (23 days) is substantially longer than for other immunoglobulin isotypes (2.5–6 days).28 Interestingly, the serum half-lives of IgG antibodies are directly related to their binding affinity for FcRn.40 Immunogenicity can also influence the clearance of an antibody which can be explained by an increased clearance of drug-ADA immune complexes. Binding of a monomeric IgG to FcgR causes internalization, but also rapid recycling of the receptor–ligand complex to the cell surface. When FcgR are cross-linked (eg, after binding to multimeric antibody complexes) receptor–ligand complexes are also internalized, but instead of recycled these complexes are retained and subsequently degraded.41 For infliximab, it was described by a two-compartment PK model that the clearance increases 2.7-fold in patients positive for ADA as compared with patients without ADA.42 Furthermore, concomitant medication could also influence antibody clearance. In a recent clinical study evaluating co-treatment of infliximab with azathioprine vs. monotherapy with either of the two drugs, showed significantly increased infliximab trough concentrations in the combination group.43 Particularly important in the setting of CD and UC is fecal loss of proteins, which can also influence the PK profile. In patients with a severe disease state, the mucosa can be denuded and ulcerated leading to a loss of barrier function and hence a loss of proteins, electrolytes, and nutrients (ie, “leaky gut”). In a recent study including patients with severe IBD, the investigators found infliximab in the feces of the patients, which they concluded could contribute to the rapid clearance of the drug, leading to an insufficient clinical response.44

Assays for Measuring Serum Drug and Anti-drug Antibody Concentrations Different academic groups and commercial companies have developed assays to measure drug and ADA concentrations in serum. Based on the sensitivity and specificity, the result of a particular assay might impact clinical decision making. Serum Drug Concentrations The most commonly used assay to measure anti-TNF drug concentrations in serum is the enzyme-linked immunosorbent assay (ELISA).45–52 Drug concentrations can also be measured in a fluid phase assay such as the radio-immunoassay (RIA),53 fluid-phase enzyme

S42 immunoassay,54 or homogenous mobility shift assay (HMSA).55 These assays have a different setup and hence different advantages relating to their implementation, practicality and sensitivity. A common factor that will greatly define their specificity is the detecting antibody that is used: either an anti-human IgG, a polyclonal antidrug antibody (from immunized goats or rabbits), a monospecific polyclonal anti-drug antibody, or a monoclonal anti-drug antibody. The advantage of a monoclonal or monospecific polyclonal anti-drug antibody is the specificity toward the anti-TNF drug, resulting in lower aspecific binding and hence a lower risk for false positives.56 A gene reporter assay was developed that can measure different anti-TNF drugs with the same assay and has a high specificity because of the use of a TNFresponsive cell line.57 Head-to-head comparisons of different assays did not show clear advantages to measure anti-TNF concentrations with solid or fluid phase assays. However, distinct differences in specificity were observed, unrelated to the type of assay.58,59 Taking into account assay cost and workload, there is however an advantage for solid phase assays which are accessible, have a high throughput and a low cost. Anti-drug Antibodies The most commonly used ADA assay is the double-antigen (a.k.a. bridging) ELISA in which the anti-TNF drug is both used as capture and detecting antibody.47,51,52,60,61 Others have developed an ELISA in which they use drug as a capture antibody and an anti-l antibody as detecting antibody.46 Since IFX is an IgG1 k antibody, this assay will be less drug-sensitive when detecting ADA: in this setting the ADA is not “bridged” between the capture and detecting antibody and thus only one free epitope is required for the drug to bind (ie, the other epitope can be occupied by drug present in the serum). A downside of this technique is that only ADA with a l constant domain will be detected and thus k ADA will be false negative. ADA can also be measured in fluid phase assays such as the RIA53,62 and HMSA.55 In the RIA, radiolabeled anti-TNF or F(ab0 )2 is used and in the HMSA, fluorescent-labeled anti-TNF is used to measure ADA concentrations. Assays were also developed that can specifically detect neutralizing ADA, using a different setup: a gene reporter assay,57 an ELISA based on the ability of HRP-linked TNF to bind to biotin-labeled anti-TNF in complex with ADA63 and a cellular based assay using a TNF-responsive cell line.64 Non-neutralizing ADA do not block anti-TNF activity and are not picked up by these assays but can also influence the efficacy of the drug by increasing clearance. Up to now it is not known whether neutralizing, nonneutralizing or both types of ADA are (equally) important. In general, measuring ADA in a fluid phase system (RIA, HMSA) has some advantages over the solid phase

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system (ELISA): eg, IgG4 monoclonal antibodies which can exchange halve molecules in vivo, leading to bispecific antibodies cannot be detected in the doubleantigen ELISA.65 Furthermore, it is believed fluid phase techniques are less susceptible to drug interference and that low affinity ADA can be detected because of less wash steps.66 On the other hand fluid phase assays are more labor intensive and in case of the RIA (using radioisotopes), less sustainable. All ADA assay formats are drug sensitive to a certain extent (generally 1 mg/mL excess anti-TNF is sufficient to block ADA detection).67 Recently, a few techniques were developed to measure ADA in the presence of drug. Typically, non-covalent complexes between drug and ADA are dissociated by lowering the pH to pH 2.5–3 after which free ADA can be detected. In a first attempt to detect therapeutic proteins in the presence of drug, Patton et al combined the acid dissociation step with the detection of free ADA in a double-antigen ELISA.68 Wang et al have developed a similar set-up with detection of free ADA after acid dissociation, in a fluid phase system using an HMSA.55 A possible problem of both techniques constitutes the reassociation of drug-ADA complexes upon neutralization. Therefore, van Schouwenburg et al developed a fluid phase assay in which drug-ADA complexes are dissociated with an acid dissociation step and reassociation with the anti-TNF is blocked by adding anti-idiotype antibody fragments (pHshift anti-idiotype antigen-binding test) after which free ADA can be detected via RIA.69 The ability to detect ADA in the presence of drug is particularly important for therapeutic proteins that are administered regularly (eg, adalimumab every other week). Until now the majority of the immunogenicity assays used for the detection of ADA (including for drug safety evaluations in most phase III clinical trials) was drug sensitive, thereby underestimating the proportion of ADA positive patients. However, the clinical relevance of low concentration ADA, not detectable in drug sensitive assays remains to be proven. Even though the performance of the assays to measure anti-TNF and ADA levels increased substantially, there is still a lack of standardization and quality control between the established tests, which could have clinical consequences upon interpretation of the results.58

Therapeutic Drug Monitoring Because of practical reasons, trough concentrations of anti-TNF monoclonal antibodies are typically used for therapeutic drug monitoring (TDM). In conjunction with the time that these drugs have been on the market, there is more data available for infliximab than for adalimumab, certolizumab pegol, and golimumab.

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Anti-drug Antibodies The reported incidence rate of ADA is highly dependent on the assay used to measure ADA, the time point of sampling (regarding drug interference) and the study population. Absolute concentrations across different assays are hard to compare given the different outcome measures (eg, Units/mL, AU/mL, mg/mL equivalents). Recently, a universal anti-adalimumab antibody standard for interlaboratory harmonization of antibody titers in patients who develop anti-adalimumab antibodies was developed.64 Since this antibody was fully characterized, tested in different assay formats and can be produced easily and reproducibly on a large scale, it can be used as a calibrator in different assays to standardize the quantification of ADA and their neutralizing capacity. The reported antibody to infliximab rates in patients treated with scheduled infusions range from 12.5 to 43% and 0.9 to 14%, respectively, for monotherapy and combination therapy with azathioprine or methotrexate.39,43,46,61,70 In the setting of episodic treatment (now obsolete), antibody to infliximab rates were higher (26– 61%).47,71–74 It is generally assumed that fully human monoclonal antibodies are less immunogenic than chimeric or murine antibodies.75 Nevertheless, adalimumab has shown to elicit an ADA response in 2.8–9.2% of the treated IBD patients.7,8,76,77 Recently antibody to adalimumab rates of 20% were reported using a drug-tolerant assay.78 Golimumab was shown to elicit an ADA response in 0.4–2.9% of the treated UC patients.11,79 In an attempt to further reduce the risk for immunogenicity, antibody derivatives were developed such as certolizumab pegol but also here an ADA response was described in 3.1–9.0% of the treated CD disease patients.9,10,80 Concomitant therapy with immunomodulators (azathioprine or methotrexate) reduces the risk for the development of ADA.43 In a meta-analysis, the use of combination therapy during maintenance infliximab therapy led to a lower risk ratio (RR) for ATI development (RR 0.6; 95% confidence interval (CI) 0.4–0.9; P ¼ 0.02) and infusion reactions (RR 0.6; 95% CI 0.4–0.8; P ¼ 0.001) as compared to patients without combination therapy.81 Recently, it was proposed by Ben-Horin et al that these immunomodulators could also be successfully used to treat away ADA.82 In this retrospective study ADA disappeared in three CD patients and two UC patients after initiation of immunomodulator therapy which was also associated with a restoration of infliximab trough concentrations and clinical response. Nevertheless, these findings need to be confirmed in a larger prospective study including a control group. Development of ADA is linked to adverse events and loss of response. For IFX, it was observed that patients with antibodies to infliximab are at risk to suffer an

S43 infusion reaction and have a shorter duration of response.6,46,72–74 In a meta-analysis, it was shown that patients with ATI have a higher risk to suffer an acute infusion reaction (RR 2.4; 95% CI 1.5–3.8; P < 0.001) as compared to patients without ATI.81 Furthermore, in the study by Baert et al, the authors investigated an arbitrarily chosen threshold to distinguish CD patients at risk for loss of response and/or an infusion reaction, based upon the concentration of antibodies to infliximab.47 Patients with antibodies to infliximab >8 mg/mL equivalents had a shorter duration of response (35 days) compared with patients with antibodies to infliximab 12 mg/mL had a longer duration of response (81.5 days) compared with patients with infliximab concentrations 5 mg/mL was predictive of normal CRP and remission and this correlation was lost when patients had anti-adalimumab antibodies >5 mg/mL.88 In the pivotal study evaluating adalimumab for induction and maintenance treatment of patients with moderate-to-severe UC, higher trough serum concentrations were observed in patients who achieved remission at week 8 and week 52 as compared with patients who did not achieve remission (respectively, 10.8 mg/mL vs. 6.2 mg/mL at week 52).8 Certolizumab Pegol Concentration–Effect Relationship In the pivotal trial evaluating certolizumab pegol for the treatment of active CD, serum concentrations of certolizumab pegol were higher in responder patients as compared with non-responder patients; however, this difference was not significant.80 Recently, a post-hoc analysis of the MUSIC trial showed that in 89 CD patients with active endoscopic disease treated with certolizumab pegol, higher serum drug concentrations at week 8 were associated with endoscopic response (P < 0.0016) and remission (P < 0.0302) at week 10 (n ¼ 45).89 Golimumab Concentration–Effect Relationship In the phase III clinical trial of golimumab for ulcerative colitis, a dose-proportional concentration–effect relationship was observed as the rates of clinical response and remission at week 6 increased with increasing quartiles of serum golimumab concentration.11

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Therapeutic Window Concept Suboptimal anti-TNF serum concentrations are associated with lower efficacy. The lower limit of the therapeutic concentration window represents the optimal concentration threshold that best discriminates remission (eg, by clinical scoring index, biomarkers, or endoscopy). This can be done by receiver operating characteristic curve analysis that will give the sensitivity and specificity of this concentration threshold in predicting remission. Except for few reports of an association between supra-therapeutic concentrations of drug and the occurrence of side effects such as skin lesions,90 the upper limit of the therapeutic concentration window should be a representation of the drug’s maximal efficacy rather than toxicity. Indeed, in a recent post-hoc analysis of the registration trial of infliximab for ulcerative colitis, it was observed that the concentration–effect relationship reached a plateau as the proportion of patients in clinical response, remission, and mucosal healing did not increase for increasing infliximab trough concentrations above a certain concentration at week 8, 30, and 54.91 Hence, dose de-escalating patients with supra-optimal drug concentrations might result in significant cost savings without a risk for loss of efficacy, if closely monitored. Therefore, we propose an adapted optimal therapeutic window, where both the lower and upper limits of the optimal concentration range need to be defined for each drug separately. Also, up to now it is unclear whether it is the peak, intermediate, trough concentration or area under the curve that correlates best with efficacy. Mainly because of practical reasons, most of the current treatment algorithms are based upon trough concentrations. Because of differences in dosing regimen and absorption, we have made a distinction between IV and SC drugs to describe their optimal therapeutic window (Fig. 1). For IV drugs, a clear distinction can be made between peak, intermediate and trough concentrations which could be used for TDM. However, for SC drugs, no clear distinction between peak, intermediate and trough concentrations can be made. Because of more frequent dosing and a slow absorption rate, a steady state concentration is reached and the time point of sampling is of lesser importance. Therefore, for SC drug, a steady state concentration within an optimal range should be targeted.

Anti-TNF Tailored Treatment This concept can be used to further optimize treatment with anti-TNF monocloncal antibodies by treating patients based on actual exposure to the drug rather than according to a standard dosing regimen. There are different periods during the treatment where this approach could be implemented, some of which prospective randomized controlled trials have already assessed different (cost-related) efficacy outcomes.

Figure 1. Pharmacokinetic profile of an intravenous (IV, red line) or subcutaneous (SC, blue line) administered anti-tumor necrosis factor agent according to a theoretical maintenance dosing regimen. Therapeutic window concept (optimal range, gray) with designation of peak, intermediate, and trough serum concentration for intravenously administered agent.

Before Treatment Initiation A molecular imaging approach where the expression of membrane-bound TNF is visualized in vivo using fluorescent labeled adalimumab and confocal laser endomicroscopy has shown promising results.92 In this prospective observational study in 25 Crohn’s disease patients, a discriminative factor based on the number of membrane-bound TNF positive cells predicted response to treatment with a sensitivity and specificity of, respectively, 92 and 85%.92 Specifically for the response to infliximab, a retrospective observational cohort study correlated the presence of pre-existing anti-murine antibodies to the lack of long-term efficacy and safety of infliximab treatment.93 Certain genetic mutations and/or polymorphisms in the apoptosis related genes of FAS-L and Caspase 9 as well as in the IBD5 locus are associated with primary non-response.94 Although more (clinical) research remains to be done, these studies have helped to understand some of the mechanisms of primary (non-) response. During the Induction Phase Low anti-TNF concentrations during the induction phase were linked to a higher risk of antibody formation to both infliximab and adalimumab.72,78,95 It can be hypothesized that exposure to suboptimal anti-TNF trough concentrations results in a more immunogenic state (less suppressed immune system).53,96 Recently, however, it was suggested that an early immunogenic response leads to a faster clearance of drug and lower exposure to drug, resulting in a lack of primary response to treatment at week 6 or 8.97 Interestingly, different groups have found an inverse correlation between pre-treatment CRP and lower anti-TNF trough concentrations during induction.50,95 In a recent post-hoc analysis of the phase III

S46 registration trial of infliximab for Crohn’s disease (ACCENT 1), it was observed that patients who had a durable sustained response to treatment throughout the first year also had significantly higher infliximab trough concentrations already at week 6 after treatment initiation.86 A recent retrospective study focused specifically on patients in whom infliximab treatment was reinitiated after a drug holiday (discontinuation of therapy for at least 6 months).98 Here, the authors found that absence of antibodies to infliximab and detectable infliximab trough concentrations during induction were associated with, respectively, safety of reinitiating therapy and long-term response.98 These results point toward early individual dose optimization; however, it is unclear if this would alter efficacy and safety outcomes in the short and longterm and results of randomized controlled trials are awaited. During the Maintenance Phase The exposure-response relationship was confirmed in different independent cohorts, and some have tried to find an optimal anti-TNF trough concentration cut-off that correlates with CRP99–101 and clinical100,102–104 or endoscopic105,106 outcomes during maintenance therapy. Therefore, it could be hypothesized that if optimal trough concentrations are targeted in individual patients, this could lead to better outcomes and have an impact on the cost-effectiveness of anti-TNF therapy. This was the research question that was investigated in the “trough concentration adapted infliximab treatment” (TAXIT) trial.107 Here, clinical responder IBD patients on infliximab maintenance therapy were first dose optimized to achieve trough concentrations within the range of 3– 7 mg/mL after which patients were randomized to continue concentration-based dosing or clinically-based dosing of infliximab. It was observed that during the optimization phase, individual dose escalation in patients with subtherapeutic infliximab trough concentrations led to a significant increase in the proportion of CD patients achieving clinical remission and a significant decrease in CRP concentrations. Meanwhile, individualized dose de-escalation in patients with supratherapeutic trough concentration resulted in significant lower drug costs without affecting remission rates. Although the primary endpoint of the randomized maintenance phase did not show an additional benefit for individualized concentration-based dosing, significantly more patients from the clinically-based dosing group needed rescue therapy to maintain response to the drug as compared to patients from the concentration-based dosing group (number needed to treat ¼ 9).107 These results suggest that it is clinically useful to optimize patients based on a treat-totrough strategy; however, it is not necessary to continue TDM at each infusion throughout the first year, after patients have been optimized.

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At time of insufficient or no response, an individualized approach based on therapeutic drug monitoring to guide treatment decisions was previously suggested70 and found to be cost-effective.108 Recently, a randomized controlled trial in 69 CD patients with secondary loss of response to infliximab showed that an individualized approach as compared to the empiric approach of doseescalation led to similar clinical outcomes, but substantially lower treatment costs (34% less).109 The cost-effectiveness of TDM is dependent on the cost of measuring drug and ADA concentrations. Therefore, to maximize the benefit of TDM, a validated and standardized test should be accessible and available at low cost. Ideally this test allows for measurements at the site of point of care, giving the physician the opportunity to intervene if necessary prior to the next administration of drug.

Conclusions In conclusion, retrospective and emerging prospective data point toward the fact that TDM can add value to current practice, by optimizing the dose in the individual patient or guide treatment decisions at times of insufficient or no response. Challenges for the future will be to further refine the optimal concentration window in the individual patient that should be targeted at the time point that is most relevant (peak – intermediate – trough). Population PK/PD modeling will aid in identifying underlying covariates that explain the observed intersubject and inter-occasion variability. Furthermore, to implement individualized TDM in standard clinical practice, rapid assays will be required that allow for quantitative measurement of anti-TNF concentrations at different time points, at the site of point of care at home or in the hospital. Funding NVC is a Postdoctoral Fellow of the Research Foundation – Flanders (FWO), Belgium; grant number 1260714N. This study was funded in part by a research grant from the Research Foundation – Flanders (FWO), Belgium; grant number G.0617.12.

Disclosures NVC received speakers and consultancy fees from Abbvie, MSD, and Janssen Biologics. AG received speakers fees from Pfizer, Janssen Biologics, and MSD and investigator initiated research grants from Pfizer. References 1. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–558.

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