Pharmacometric models to improve therapeutic drug monitoring of monoclonal antibodies in the treatment of inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are chronic, relapsing, inflammatory conditions of the gastrointestinal (GI) tract. Ulcerative colitis (UC) and Crohn's disease (CD) are the primary subtypes of IBD. Although the etiology remains incompletely understood, it is generally accepted that IBD is the result of an inappropriate host response to environmental factors in genetically susceptible individuals. In Western Europe, prevalence of UC is estimated 120-200 per 100,000 persons and 50-200 per 100,000 for CD. Patients are usually diagnosed with UC and CD in their 20s and 30s, but all age groups can be affected. Treatment of IBD focuses on inducing clinical remission and preventing relapses. Conventionally, a step-up strategy is used, in which therapy is intensified as disease worsens. Traditionally, IBD is handled with corticosteroids, 5-aminosalicylates and immunomodulators such as methotrexate and the thiopurines azathioprine and 6-mercaptopurine. In the late 1990s, the armamentarium of treatment options was extended with the introduction of tumor necrosis factor-α (TNF) antagonists. The proinflammatory cytokine TNF plays a key role in the intestinal inflammatory cascade. Neutralizing TNF with a synthetic monoclonal antibody (MA) has been shown to diminish inflammation and induce apoptosis of TNF-producing immune cells. Currently, the European Medicines Agency (EMA) has approved five TNF antagonists for the treatment of IBD: Remicade® (infliximab, IFX), Humira® (adalimumab, ADM), Simponi® (golimumab, GLM) and two IFX biosimilars Inflectra® and Remsima®. IFX is an intravenously administered chimeric MA4,7. ADM and GLM are both subcutaneously administered human MAs. Anti-TNF treatment cost in patients with IBD is estimated at 20,000 euro/year. Although biologicals have revolutionized IBD treatment, up to 40% of the patients who initially respond to anti-TNF treatment will lose response over one year. The annual risk for loss of response (LOR) is estimated to be 13% for IFX and 24% for ADM. LOR is mainly attributed to inter- and intra-individual factors that influence the pharmacokinetic (PK) profile. The formation of anti-drug antibodies (ADAs) is one of the causes of an accelerated drug clearance and results in a lower drug serum concentration and thereby undermines the therapeutic efficacy. Empirically, when a patient becomes refractory to anti-TNF treatment, treatment is intensified and if this fails, treatment is switched to another anti-TNF drug. Instead of this currently used "algorithm-based strategy", an alternative strategy was postulated to deal with LOR. This new "testing-based approach" relies on therapeutic drug monitoring (TDM), where monitoring of individual serum concentrations carries the potential to improve (cost) efficacy of the biopharmaceutical. Different post hoc analyses of phase III trials of IFX in CD (ACCENT1) and UC (ACT1 and 2) and a comparative study of azathioprine, IFX and combination in CD (SONIC) have shown a positive exposure-effect relationship between IFX serum trough concentration (TC) and clinical outcomes like response, remission and mucosal healing in IBD patients. From these data, an optimal IFX TC window between 3-7 μg/mL has been proposed. The Trough concentration Adapted infliXImab Treatment (TAXIT) study, a single-center randomized controlled trial (RCT), evaluated personalized IFX dosing based on individual TC in a cohort of 263 IBD responder patients receiving maintenance IFX. The optimization phase of TAXIT showed that targeting IFX TC within the 3-7 μg/mL window resulted in a more efficient use of the drug: dose escalation in CD patients with a suboptimal IFX TC resulted in a higher proportion of patients in clinical remission and a decrease in C-reactive protein (CRP) level. On the other hand, dose reduction in CD and UC patients with a supraoptimal IFX TC led to cost savings of up to 28%. A limitation of the study is that a fixed TC window was used. Defining optimal peak, intermediate and trough concentration windows for each individual patient would contribute to strengthening the position of TDM in clinical practice. However, a precise description of the PK and pharmacodynamics (PD) is a prerequisite to individual dosing and dose adjustment. The PK and PD of therapeutic MAs are potentially influenced by many factors, such as sex, weight, age, disease type and severity, ADA, albumin, co-medication and other yet unidentified factors. Population PK/PD modeling can be used to identify these determinants and help to explain the observed PK/PD variability. To predict individualized drug dosing regimes and dose adjustments, a PK/PD model that incorporates patients characteristics can be used. The predicted dosing algorithm should minimize variances in patient drug exposure to achieve a favorable impact on (cost) efficacy and safety. Therefore, a next step towards a better management of the treatment patients with IBD is the establishment of PK/PD models of anti-TNF drugs, in which variables of each patient at a certain moment will be used to predict the optimal dosing regimen in an individual patient, in order to achieve optimal drug exposure that is linked to a favorable short- and long-term efficacy outcome.

Publication year:2019

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