Accelerated Clearance of Infliximab is Associated With Treatment Failure in Patients With Corticosteroid-Refractory Acute Ulcerative Colitis

Accelerated Clearance of Infliximab is Associated With Treatment Failure in Patients With... Abstract Background and Aims A significant proportion of patients with corticosteroid-refractory acute ulcerative colitis [UC] fail therapy. We aimed to assess the pharmacokinetics [PK] of infliximab [IFX] in patients with corticosteroid-refractory acute UC and determine the association between induction IFX PK and short- and long-term therapy outcome. Methods A population PK model was developed using data from 51 patients with UC [n = 42] and Crohn’s disease [n = 9]. A subset of patients [n = 36] with acute corticosteroid-refractory UC (median Mayo score 11 [range 8–12]; 33 of 36 hospitalized; median corticosteroid dose at study entry 50mg prednisolone equivalent IV/oral) commencing IFX were studied to assess further correlations between PK from the first induction dose and therapy outcomes. Serial induction drug levels from the 36 UC patients were collected, facilitating population-based PK analysis. IFX and antibodies-to-infliximab [ATIs] concentrations were determined using AnsrTM IFX assay [Prometheus Inc.]. Results The Week 14 clinical response and Week 54 corticosteroid-free remission rates were 78% [28/36] and 53% [19/36], respectively. The estimated effective IFX half-life [T1/2] (median [range]) and clearance (median [range]) were 8.42 [3.94–22.03] days and 0.50 [0.19–1.41] L/day respectively. Longer induction IFX T1/2 and lower clearance were associated with the Week 14 clinical response [p = 0.005] and the Week 54 corticosteroid-free remission rates [p = 0.007]. Conclusions Accelerated IFX clearance occurs in corticosteroid-refractory acute UC and is associated with therapy failure. These data support the use of accelerated IFX induction regimens in patients with corticosteroid-refractory acute UC failing conventional dosing regimens. Infliximab, ulcerative colitis, pharmacokinetics 1. Introduction The pro-inflammatory cytokine tumour necrosis factor-α [TNF] plays an important role in the pathogenesis of ulcerative colitis [UC] and Crohn’s Disease [CD]. Intravenous administration of infliximab [IFX], a chimeric, IgG-1 monoclonal antibody to TNF, has been shown to be effective in the therapy of patients with moderate to severe UC and CD failing conventional therapy with corticosteroids and immunomodulator therapies.1,2 For patients with corticosteroid-refractory moderate to severe ulcerative colitis, induction IFX therapy is associated with less favourable outcomes, including colectomy.3,4 Despite the efficacy of anti-TNF therapies, a significant proportion of patients do not experience a therapeutic response, with one hypothesized mechanism of failure being increased IFX clearance, with consequent decreased drug exposure. While a similar IFX half-life [T1/2] has been reported in population-based studies of UC and CD,5,6 potentially important pharmacokinetic [PK] differences exist between these conditions, as evidenced by reports showing a greater proportion of UC compared with CD patients having undetectable trough IFX levels during maintenance therapy.7,8 UC disease severity may also be an important factor affecting IFX PK, with lower serum IFX concentrations on Day 14 post therapy initiation observed in patients with corticosteroid-refractory acute severe, compared with moderately active, UC.9 Data on the PK of IFX in corticosteroid-refractory acute UC remain scarce and there is a paucity of information on the PK of IFX during induction therapy. We aimed to characterize IFX PK during induction in patients with corticosteroid-refractory acute UC, and to determine covariates associated with drug clearance. We also explored the association between induction IFX PK parameters and induction and maintenance therapy outcomes. 2. Methods 2.1. Patient population The diagnosis of UC was made using established clinical, endoscopic and histological criteria.10,11 Baseline UC disease activity was measured by the Mayo score.12 In a retrospective study, a cohort of acute UC patients [n = 36] refractory to corticosteroids commencing three-dose induction IFX treatment at Mount Sinai Hospital, Toronto were studied [acute UC cohort]. Of the 36 included patients, 33 [92%] were hospitalized due to UC disease activity. Serial serum samples [median 5, range 1–42 samples] were drawn during IFX induction to facilitate a population-based IFX PK analysis. There was no specific protocol specifying at what time point/s induction serum samples were to be collected. IFX was administered as per the standard protocol, with induction therapy of 5 mg/kg at 0, 2 and 6 weeks.1 Patients responding to induction received IFX 5 mg/kg at scheduled intervals of 8 weeks. Adjustment of the infusion interval and/or an increment of the dose to 10 mg/kg IFX were undertaken at the discretion of the treating physician. Concomitant additional treatment with mesalamine and azathioprine were administered as indicated. The study was approved by the institutional Research Ethics Board, and all patients gave written informed consent. 2.2. Clinical evaluations Clinical evaluations included age, gender, disease duration, concurrent use of mesalamine and azathioprine, and dose and duration of corticosteroids prior to the commencement of IFX. Tuberculosis was excluded in all patients by a negative purified protein derivative [PPD] skin test and a normal chest radiograph. Patients were assessed at baseline and thereafter at Weeks 14 and 54 after the commencement of IFX. Complete blood count, chemistry tests [liver and renal profile], serum albumin, and C-reactive protein [CRP] estimations were performed at baseline. Baseline UC disease activity was measured by the Mayo score. Outcome of IFX induction therapy was assessed as Week 14, and outcome of maintenance therapy was assessed at Week 54. 2.3. Measurement of serum infliximab and antibodies to infliximab concentrations Serum concentrations of IFX and antibodies-to-infliximab [ATIs] were evaluated in serial serum samples drawn during IFX induction to facilitate a population-based IFX PK analysis. The AnsrTM IFX assay [Prometheus Inc., San Diego, CA] was used to determine serum IFX and ATI concentrations.13,14 2.4. Pharmacokinetic modeling To ensure the validity of the PK model utilized in the study, summary PK parameters were generated for IFX using a pooled cohort of n = 51 inflammatory bowel disease [IBD] patients [PK cohort] with sequential sampling [Table 1]. Infliximab concentration time data were fit using NONMEM 7 version 2.0 [Icon Development Solutions, Dublin Ireland] with the first-order conditional estimation [FOCE] method.15 The log transform both-sides approach was implemented, and observations that were below the limit of assay quantification were included using the M3 method.16 Standard model-building methods were used, and models were evaluated with standard goodness-of-fit assessments.17 The effects of covariates were first evaluated graphically using Xpose4,18 then evaluated serially in the model. The likelihood ratio test was used to assess nested models. Covariate acceptance was set to p < 0.005 during initial evaluations and at p < 0.001 for backwards elimination and development of the final model. Model evaluation included assessment of parameter precision through standard errors of the estimates, diagnostic goodness-of-fit plots, and a visual predictive check.19 Parameter shrinkage was also evaluated.20 Table 1. Baseline characteristics of the acute UC cohort [n = 36] and the pooled IBD cohort [n = 51] used to validate the PK model [PK cohort]. Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Continuous data are presented as median [min–max]. Where no range is provided, variables represent raw numbers. Mayo score data reported for PK cohort [n=51] is derived from UC patients within this cohort. View Large Table 1. Baseline characteristics of the acute UC cohort [n = 36] and the pooled IBD cohort [n = 51] used to validate the PK model [PK cohort]. Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Continuous data are presented as median [min–max]. Where no range is provided, variables represent raw numbers. Mayo score data reported for PK cohort [n=51] is derived from UC patients within this cohort. View Large 2.5. Study endpoints Evaluation of clinical outcomes was confined to the acute UC cohort [n = 36]. The clinical response was documented at Week 14 [induction therapy outcome] and defined as the impression of the treating physician of a clinical response and the continued utilization of IFX therapy post induction. Corticosteroid-free remission rates were documented at Week 54 [maintenance therapy outcome]. Corticosteroid-free remission was defined as a Mayo score of 0 and the absence of corticosteroid treatment. Infliximab PK during induction and maintenance therapy and covariates associated with drug clearance were evaluated. Infliximab Day 1 induction PK parameters, including effective terminal T1/2 and drug clearance were quantified in the acute UC cohort [n = 36] and their association with induction and maintenance therapy outcomes evaluated. 2.6. Statistical analysis Continuous variables are presented as medians and ranges. Comparisons of differences between groups were assessed by the analysis of variance [ANOVA] or the Kruskal–Wallis ANOVA on ranks as appropriate. Statistical analysis was performed by using SAS [version 9.1.2; SAS Institute, Cary, North Carolina, USA]. 3. Results 3.1. Baseline demographics The baseline characteristics of the acute UC cohort [n = 36] and of the PK cohort [n = 51] are shown in Table 1. For the acute UC cohort [n = 36], the median Mayo score in the study cohort was 11 [range 8–12], with the median corticosteroid dose [PO/IV] at study entry being 50 mg prednisone equivalents. The median endoscopic Mayo score at study entry was 3 [range 2–3]. Of the 36 patients in the acute UC cohort, 33 [92%] had extensive colitis, with the remainder having left-sided colitis. The serum albumin concentration (median [range]) was 33 g/L [24–48]. The median baseline serum CRP concentration was 33 mg/L [range, 1–240]. Of the 36 patients, 9 [25%] required a colectomy during follow-up. 3.2. Induction infliximab pharmacokinetics The final PK model parameters derived from 51 patients [PK cohort] are described in Supplementary Table 1. Because IFX PK are described using a two-compartment model, three different T1/2 values can be computed: the alpha T1/2, which reflects the duration of the initial fast fall-off of IFX after the end of infusion, the beta T1/2, which reflects the slower fall-off of IFX, and an effective T1/2, which combines the two prior values and reflects the contribution of each phase [fast and slow fall-off]. Thus the effective T1/2 provides a more clinically relevant description of the duration of time that IFX will remain measurable after an infusion. The estimated effective IFX T1/2 (median [range]) was 8.42 [3.91–22.03] days, with alpha and beta T1/2 (median [range]) estimates of 2.48 [1.19–3.76] days and 15.33 [7.81–52.48] days, respectively [Figure 1A]. The estimated IFX clearance (median [range]) was 0.50 [0.19–1.41] L/day [Figure 1B]. Induction ATIs were demonstrated in only four subjects [11%] in the study cohort. There was a relationship between serum albumin concentration and induction IFX PK, with a shorter effective IFX T1/2 [p = 0.029] and increased IFX clearance [p = 0.012] in individuals with a low serum albumin concentration [of <35 g/L versus ≥35 g/L] [Figure 2A and B]. Linear regression models demonstrated a significant inverse association between serum albumin concentration and IFX clearance. A significant association between CRP concentration and IFX clearance was also demonstrated using linear regression [Supplementary Figure 1A and B]. Time from initiation of IFX therapy was inversely associated with IFX clearance. Clearance was highest during the induction phase of therapy; in individuals who avoided colectomy, IFX clearance appeared to slow down over time [Figure 3]. The inverse relationship between time on therapy and IFX drug clearance was reversed in the presence of ATIs, with IFX clearance increasing over time in this subgroup of patients [Supplementary Figure 2]. Additional covariates identified as associated with IFX clearance were the presence of ATIs, weight, inter-compartmental clearance and central and peripheral volumes of distribution [Supplementary Table 1]. Due to the small number of patients receiving concomitant immunomodulators, their impact on induction IFX PK could not be assessed. Figure 1. View largeDownload slide Infliximab induction pharmacokinetic [PK] parameters in the acute UC cohort [n = 36 subjects]. Figure 1. View largeDownload slide Infliximab induction pharmacokinetic [PK] parameters in the acute UC cohort [n = 36 subjects]. Figure 2. View largeDownload slide Association between infliximab [IFX] pharmacokinetic [PK] parameters and serum albumin concentration in the acute UC cohort [n = 36 subjects]. Figure 2. View largeDownload slide Association between infliximab [IFX] pharmacokinetic [PK] parameters and serum albumin concentration in the acute UC cohort [n = 36 subjects]. Figure 3. View largeDownload slide Infliximab [IFX] clearance over time in the acute UC cohort [n = 36 subjects] by colectomy status. Figure 3. View largeDownload slide Infliximab [IFX] clearance over time in the acute UC cohort [n = 36 subjects] by colectomy status. 3.3. Association between infliximab pharmacokinetics and outcome of induction therapy The Week 14 clinical response rate was 78% [28/36]. Induction IFX PK parameters were associated with the outcome of induction therapy. A longer effective IFX T1/2 [p = 0.005] and reduced IFX clearance [p = 0.002] were observed when comparing induction responders with subjects who failed to achieve an induction response, respectively [Figure 4A and B]. There was a non-significant trend toward higher Weeks 2 and 6 trough IFX levels in subjects who did not require a colectomy, compared with those who proceeded to colectomy [Supplementary Figure 3]. A representative example of a study subject exhibiting rapid IFX clearance and induction failure is shown in Supplementary Figure 4. Figure 4. View largeDownload slide Induction pharmacokinetic [PK] parameters according to induction therapy outcome in the acute UC cohort [n = 36 subjects]. Figure 4. View largeDownload slide Induction pharmacokinetic [PK] parameters according to induction therapy outcome in the acute UC cohort [n = 36 subjects]. 3.4. Association between infliximab pharmacokinetics and outcome of maintenance therapy The Week 54 corticosteroid-free remission rate was 53% [19/36]. Induction IFX PK were associated with long-term therapy outcome, with a significantly longer IFX T1/2 [p = 0.007] and lower IFX clearance [p = 0.009] in individuals who achieved compared with those who failed to achieve corticosteroid-free remission at Week 54 [Figure 5A and B]. There was a trend toward increasing IFX T1/2 and reducing IFX clearance, moving from the induction failure group who did not proceed to maintenance therapy, through the induction responder group who failed maintenance therapy, to the induction responder group who remained in remission at one year. IFX T1/2 was significantly longer and IFX clearance lower in induction responders who remained in remission compared with induction failures who did not receive maintenance therapy [p = 0.002 and p = 0.003, respectively] [Figure 5C and D]. Of the 36 patients in the acute UC cohort, 6 [17%] were found to be ATI positive during study follow-up. Figure 5. View largeDownload slide Relationship between induction infliximab [IFX] pharmacokinetic [PK] parameters and corticosteroid-free remission at Week 54 and combined induction and maintenance therapy outcomes in the acute UC cohort [n = 36 subjects]. Figure 5. View largeDownload slide Relationship between induction infliximab [IFX] pharmacokinetic [PK] parameters and corticosteroid-free remission at Week 54 and combined induction and maintenance therapy outcomes in the acute UC cohort [n = 36 subjects]. 4. Discussion Although IFX is an important component of the therapeutic armament in acute UC, outcomes from clinical trials have been variable.1,21,22 Differences in the trough IFX concentrations when comparing UC and CD,7,8 and the lesser therapy response rates in severe UC patient populations, suggest that IFX PK may be an important variable contributing to therapy failure.22 We studied the PK of IFX in a cohort of patients with corticosteroid-refractory acute UC. Of the 36 patients in the study cohort, 33 were hospitalized. We evaluated whether induction IFX PK parameters were associated with short- and long-term therapy outcomes. We confirmed that there was a significantly increased IFX clearance and shorter IFX T1/2 in our acute UC cohort, compared with previous estimates derived from ambulatory cohorts with moderately active UC. We also demonstrated a relationship between induction IFX PK parameters and therapy outcome, with decreased IFX T1/2 and increased IFX clearance associated with both induction and maintenance therapy failure. Population-based PK analyses using data from the ACT 1 and 2 randomized control trials generated an estimated IFX T1/2 in UC of 14 days.6 ACT 1 and 2 included UC patients with moderately severe disease (median Mayo score of 8 [range 4–12], 56% utilizing concomitant corticosteroids).1 A similar population-based PK analysis using data from the ACCENT 1 randomized controlled trial, which included patients with moderately active CD, generated an estimated IFX T1/2 of 12.4 days.2,5 The cohort of patients evaluated in this report had significantly more severe disease [median Mayo score 11; 33 of 36 hospitalized; median corticosteroid dose at study entry 50 mg prednisone equivalents] than those evaluated in the ACT 1 and 2 trials. We demonstrated IFX PK to differ significantly in our cohort compared with previously reported IFX PK.5,6 The effective IFX T1/2 estimate in our cohort was 8.42 days. Our data are in concordance with those from Ungar et al., which demonstrated Day 14 trough IFX levels to be significantly lower in patients with acute severe UC compared with in patients with moderately severe UC.9 The shorter IFX T1/2 observed in more severe UC cohorts is likely reflective of an increased inflammatory disease burden, which is increasingly being recognised as a factor that influences IFX clearance and consequently drug T1/2. The PK and pharmacodynamics of therapeutic monoclonal antibodies are complex and depend on antibody structure, the characteristics of the target antigen, patient factors, and disease-related factors. Pharmacokinetic–pharmacodynamic factors are interrelated and play an important role in understanding the association between drug concentration and therapeutic response. While determinants of IFX PK remain poorly understood, a number of factors have been shown to increase IFX clearance, including inflammatory burden of disease [high baseline TNF], low albumin, high body weight, the presence of ATIs, and lack of concurrent immunomodulator use.23 Substantiating previous data, we demonstrated that decreased serum albumin and increased CRP concentration were associated with increased IFX clearance and decreased drug T1/2.24,25 These associations support the hypothesis that inflammatory burden is an important determinant of IFX PK in IBD cohorts. The concept of inflammatory burden refers to intestinal ‘TNF antigen load’, which if significantly elevated, may result in increased drug clearance by antigen-dependant pathways. In addition to its association with inflammatory burden, a decreased serum albumin concentration may be a manifestation of a protein-losing enteropathy, which could represent an additional mechanism of increased IFX clearance in moderate-to-severe UC. Support for this hypothesis was provided by a report of elevated fecal IFX concentrations in subjects with acute severe UC failing induction therapy.26 Immunogenicity is an issue associated with the use of therapeutic monoclonal antibodies. Development of ATIs increases drug clearance by the formation of immune complexes, which accelerate drug clearance by the reticuloendothelial system, or impair binding to the target antigen.23 The presence of ATIs in the maintenance phase of therapy has previously been shown to increase IFX clearance in UC and CD5,6; however, little is known about the influence of ATIs on IFX PK during induction therapy. ATI estimations in this report were performed using a homogeneous mobility shift assay [Prometheus Laboratories, San Diego, CA].27 In our cohort, ATI formation was uncommon during induction, with only 11% of subjects found to be ATI positive. The study PK model demonstrated ATIs to increase drug clearance significantly. With the initial appearance of ATIs, the effect on clearance is minor [generally due to low titers], but this impact increases over time and is particularly relevant in the maintenance phase of therapy. The prevalence of induction ATIs in our report differed from that in the two other studies that examined induction ATI rates in patients with acute UC.9,27 This may be explained by a number of factors, including the differences in the assays utilized to detect ATIs [although all assays were drug tolerant], relatively small patient cohorts, study population heterogeneity, and differing time points at which induction ATIs were assessed. Concurrent use of immunomodulators has been shown to increase the serum concentration of IFX and to decrease IFX clearance.28–30 Only 4 of the 36 patients in the acute UC cohort studied were receiving concurrent immunomodulators; therefore, we could not assess the effect of immunomodulators on IFX clearance in this study. An important finding of the study was the association between induction IFX PK parameters and the outcome of induction and maintenance therapy. Accelerated IFX clearance during induction with a shorter IFX T1/2was associated with reduced induction [Week 14] clinical response and maintenance [Week 54] corticosteroid-free remission rates. These data are in concordance with a report from Brandse et al., which demonstrated lower Week 6 serum IFX concentrations in primary non-responders compared with in responders in a cohort with moderate-to-severe UC receiving IFX induction.27 The data we report provide mechanistic information that suggest that accelerated IFX dosing may improve the outcome of corticosteroid-refractory acute UC; however, it is important to emphasize that the data are associative rather than causative. Accelerated IFX clearance may be a mechanism of therapy failure in corticosteroid-refractory acute UC. It is also possible, however, that adverse induction IFX PK parameters are merely a marker of severe disease and consequently of patients likely to fail IFX therapy irrespective of the induction schedule utilized. Three studies have directly examined the clinical outcome of accelerated IFX dosing in acute UC with contrasting results. Gibson et al. performed a retrospective evaluation of n = 50 hospitalized patients with corticosteroid-refractory acute severe UC treated with accelerated [n = 15] and standard [n = 35] IFX induction regimens. Disease severity at baseline was similar in the accelerated dosing subgroup to that in the standard dosing subgroup. Significantly reduced 3- and 6-month colectomy rates were observed in the accelerated dosing subgroup, compared with the standard induction dosing subgroup.31 Choy et al. provided further support for this therapeutic approach in an abstract publication that compared the outcome of accelerated and standard IFX dosing in corticosteroid-refractory acute severe UC. The 3- and 12-month colectomy rates for the accelerated and standard dosing groups were similar, despite individuals receiving accelerated IFX dosing having more severe baseline disease.32 In contrast, data presented in abstract form by Govani et al. did not demonstrate a benefit of accelerated IFX dosing in a cohort [n = 57] of hospitalized patients with acute severe UC.33 The available clinical data describing the outcome of accelerated compared with standard IFX dosing for acute corticosteroid-refractory UC has limitations. It is retrospective in nature and involves small cohorts. In addition, in the reports by Choy et al. and Govani et al., the accelerated dosing group had more severe baseline disease than the standard dosing group, making comparison of outcomes between these groups difficult.32,33 It is our view that, the IFX PK data we report, along with the available observational clinical data, support the use of accelerated IFX induction in selected patients with corticosteroid-refractory acute severe UC. Prospective trials are required in order to definitively examine the impact on therapy outcome of accelerated compared with conventional IFX dosing on this UC patient subgroup. In summary, we have demonstrated that patients with corticosteroid-refractory acute UC have increased IFX clearance and a shorter IFX T1/2 than previously studied moderately active outpatient UC cohorts. Induction IFX PK parameters are associated with induction and maintenance therapy outcomes. Decreased serum albumin and increased CRP concentrations are associated with accelerated IFX clearance during induction, substantiating inflammatory disease burden as an important determinant of IFX PK. These mechanistic data support the use of accelerated IFX induction regimens in patients with corticosteroid-refractory acute UC who are failing to achieve an adequate therapeutic response to conventional dosing schedules. Prospective trials in UC are required in order to formally evaluate the efficacy and safety of accelerated versus conventional IFX dosing regimens, and to define patient subgroups most likely to benefit from these treatment strategies. Funding DK is a recipient of a CIHR / Canadian Association of Gastroenterology [CAG] / Abbvie IBD Fellowship. MSS is supported by the Gale and Graham Wright Chair in Digestive Diseases at Mount Sinai Hospital, Toronto. Conflict of Interest The authors have no conflicts to disclose. The authors would like to disclose the support provided by Prometheus Laboratories, San Diego, CA for this study by way of their performance of infliximab therapeutic drug monitoring assessments. Author Contributions D.K.: patient recruitment, data collection, study design, data analysis, writing up of manuscript; S.M.: patient recruitment, data collection and review of manuscript; D.R.M.: study design, data analysis, writing up of manuscript; M.S.S.: study design, data analysis, writing up of manuscript. Supplementary Data Supplementary data are available at ECCO-JCC online. Acknowledgments The authors would like to acknowledge the pivotal contribution of the late Dr Gordon R Greenberg to the conception, design and conduct of this study. They would also like to acknowledge his invaluable contribution to the analysis and interpretation of data contained within the study. We would also like to acknowledge the significant contribution of Anna Iacono to the conduct of this study. Conference presentation: Preliminary data from this study were presented at Digestive Disease Week, San Diego, May 2012. [Accelerated Clearance of Serum Infliximab During Induction Therapy for Acute Ulcerative Colitis is Associated with Treatment Failure. Gastroenterology 142 [5], S-384-S-385]. References 1. Rutgeerts P , Sandborn WJ , Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis . N Engl J Med 2005 ; 353 : 2462 – 76 . Google Scholar CrossRef Search ADS PubMed 2. Hanauer SB , Feagan BG , Lichtenstein GR et al. ; ACCENT I Study Group . Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial . Lancet 2002 ; 359 : 1541 – 9 . Google Scholar CrossRef Search ADS PubMed 3. Gustavsson A , Halfvarson J , Magnuson A , Sandberg-Gertzén H , Tysk C , Järnerot G . Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era . 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Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum . J Immunol Methods 2012 ; 382 : 177 – 88 . Google Scholar CrossRef Search ADS PubMed 15. Boeckmann AJB , Sheiner LB , Beal SL. NONMEM Users Guide. Parts I–VIII . Ellicott City, MD, USA : Icon Development Solutions ; 2012 . 16. Beal SL . Ways to fit a PK model with some data below the quantification limit . J Pharmacokinet Pharmacodyn 2001 ; 28 : 481 – 504 . Google Scholar CrossRef Search ADS PubMed 17. Mandema JW , Verotta D , Sheiner LB . Building population pharmacokinetic–pharmacodynamic models. I. Models for covariate effects . J Pharmacokinet Biopharm 1992 ; 20 : 511 – 28 . Google Scholar CrossRef Search ADS PubMed 18. Jonsson EN , Karlsson MO . Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM . Comput Methods Programs Biomed 1999 ; 58 : 51 – 64 . 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Clin Pharmacol Ther 2012 ; 91 : 635 – 46 . Google Scholar CrossRef Search ADS PubMed 24. Fasanmade AA , Adedokun OJ , Olson A , Strauss R , Davis HM . Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis . Int J Clin Pharmacol Ther 2010 ; 48 : 297 – 308 . Google Scholar CrossRef Search ADS PubMed 25. Ternant D , Berkane Z , Picon L et al. Assessment of the influence of inflammation and FCGR3A genotype on infliximab pharmacokinetics and time to relapse in patients with Crohn’s disease . Clin Pharmacokinet 2015 ; 54 : 551 – 62 . Google Scholar CrossRef Search ADS PubMed 26. Brandse JF , van den Brink GR , Wildenberg ME et al. Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis . Gastroenterology 2015 ; 149 : 350 – 5 .e2. Google Scholar CrossRef Search ADS PubMed 27. Brandse JF , Mathôt RA , van der Kleij D et al. Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis . Clin Gastroenterol Hepatol 2016 ; 14 : 251 – 8 .e1–2. Google Scholar CrossRef Search ADS PubMed 28. Baert F , Noman M , Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease . N Engl J Med 2003 ; 348 : 601 – 8 . Google Scholar CrossRef Search ADS PubMed 29. Lichtenstein GR , Diamond RH , Wagner CL et al. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials . Aliment Pharmacol Ther 2009 ; 30 : 210 – 26 . Google Scholar CrossRef Search ADS PubMed 30. Feagan BG , McDonald JW , Panaccione R et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease . Gastroenterology 2014 ; 146 : 681 – 688 .e1. Google Scholar CrossRef Search ADS PubMed 31. Gibson DJ , Heetun ZS , Redmond CE et al. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis . Clin Gastroenterol Hepatol 2015 ; 13 : 330 – 335 .e1. Google Scholar CrossRef Search ADS PubMed 32. Choy M , Seah D , Gorelik A et al. P313 Comparison of accelerated infliximab induction versus standard induction treatment in acute severe ulcerative colitis . In: Poster Presentations: Clinical: Therapy & Observation, 11th Congress of ECCO, 2016; Amsterdam . 33. Govani SM , Waljee AK , Stidham RW , Higgins P , Hardiman K . 516 Accelerated dosing of infliximab prevents colectomy within 90 days in only half of patients with severe ulcerative colitis . Gastroenterology 2016 ; 150 : S106 . Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Accelerated Clearance of Infliximab is Associated With Treatment Failure in Patients With Corticosteroid-Refractory Acute Ulcerative Colitis

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
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10.1093/ecco-jcc/jjy028
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Abstract

Abstract Background and Aims A significant proportion of patients with corticosteroid-refractory acute ulcerative colitis [UC] fail therapy. We aimed to assess the pharmacokinetics [PK] of infliximab [IFX] in patients with corticosteroid-refractory acute UC and determine the association between induction IFX PK and short- and long-term therapy outcome. Methods A population PK model was developed using data from 51 patients with UC [n = 42] and Crohn’s disease [n = 9]. A subset of patients [n = 36] with acute corticosteroid-refractory UC (median Mayo score 11 [range 8–12]; 33 of 36 hospitalized; median corticosteroid dose at study entry 50mg prednisolone equivalent IV/oral) commencing IFX were studied to assess further correlations between PK from the first induction dose and therapy outcomes. Serial induction drug levels from the 36 UC patients were collected, facilitating population-based PK analysis. IFX and antibodies-to-infliximab [ATIs] concentrations were determined using AnsrTM IFX assay [Prometheus Inc.]. Results The Week 14 clinical response and Week 54 corticosteroid-free remission rates were 78% [28/36] and 53% [19/36], respectively. The estimated effective IFX half-life [T1/2] (median [range]) and clearance (median [range]) were 8.42 [3.94–22.03] days and 0.50 [0.19–1.41] L/day respectively. Longer induction IFX T1/2 and lower clearance were associated with the Week 14 clinical response [p = 0.005] and the Week 54 corticosteroid-free remission rates [p = 0.007]. Conclusions Accelerated IFX clearance occurs in corticosteroid-refractory acute UC and is associated with therapy failure. These data support the use of accelerated IFX induction regimens in patients with corticosteroid-refractory acute UC failing conventional dosing regimens. Infliximab, ulcerative colitis, pharmacokinetics 1. Introduction The pro-inflammatory cytokine tumour necrosis factor-α [TNF] plays an important role in the pathogenesis of ulcerative colitis [UC] and Crohn’s Disease [CD]. Intravenous administration of infliximab [IFX], a chimeric, IgG-1 monoclonal antibody to TNF, has been shown to be effective in the therapy of patients with moderate to severe UC and CD failing conventional therapy with corticosteroids and immunomodulator therapies.1,2 For patients with corticosteroid-refractory moderate to severe ulcerative colitis, induction IFX therapy is associated with less favourable outcomes, including colectomy.3,4 Despite the efficacy of anti-TNF therapies, a significant proportion of patients do not experience a therapeutic response, with one hypothesized mechanism of failure being increased IFX clearance, with consequent decreased drug exposure. While a similar IFX half-life [T1/2] has been reported in population-based studies of UC and CD,5,6 potentially important pharmacokinetic [PK] differences exist between these conditions, as evidenced by reports showing a greater proportion of UC compared with CD patients having undetectable trough IFX levels during maintenance therapy.7,8 UC disease severity may also be an important factor affecting IFX PK, with lower serum IFX concentrations on Day 14 post therapy initiation observed in patients with corticosteroid-refractory acute severe, compared with moderately active, UC.9 Data on the PK of IFX in corticosteroid-refractory acute UC remain scarce and there is a paucity of information on the PK of IFX during induction therapy. We aimed to characterize IFX PK during induction in patients with corticosteroid-refractory acute UC, and to determine covariates associated with drug clearance. We also explored the association between induction IFX PK parameters and induction and maintenance therapy outcomes. 2. Methods 2.1. Patient population The diagnosis of UC was made using established clinical, endoscopic and histological criteria.10,11 Baseline UC disease activity was measured by the Mayo score.12 In a retrospective study, a cohort of acute UC patients [n = 36] refractory to corticosteroids commencing three-dose induction IFX treatment at Mount Sinai Hospital, Toronto were studied [acute UC cohort]. Of the 36 included patients, 33 [92%] were hospitalized due to UC disease activity. Serial serum samples [median 5, range 1–42 samples] were drawn during IFX induction to facilitate a population-based IFX PK analysis. There was no specific protocol specifying at what time point/s induction serum samples were to be collected. IFX was administered as per the standard protocol, with induction therapy of 5 mg/kg at 0, 2 and 6 weeks.1 Patients responding to induction received IFX 5 mg/kg at scheduled intervals of 8 weeks. Adjustment of the infusion interval and/or an increment of the dose to 10 mg/kg IFX were undertaken at the discretion of the treating physician. Concomitant additional treatment with mesalamine and azathioprine were administered as indicated. The study was approved by the institutional Research Ethics Board, and all patients gave written informed consent. 2.2. Clinical evaluations Clinical evaluations included age, gender, disease duration, concurrent use of mesalamine and azathioprine, and dose and duration of corticosteroids prior to the commencement of IFX. Tuberculosis was excluded in all patients by a negative purified protein derivative [PPD] skin test and a normal chest radiograph. Patients were assessed at baseline and thereafter at Weeks 14 and 54 after the commencement of IFX. Complete blood count, chemistry tests [liver and renal profile], serum albumin, and C-reactive protein [CRP] estimations were performed at baseline. Baseline UC disease activity was measured by the Mayo score. Outcome of IFX induction therapy was assessed as Week 14, and outcome of maintenance therapy was assessed at Week 54. 2.3. Measurement of serum infliximab and antibodies to infliximab concentrations Serum concentrations of IFX and antibodies-to-infliximab [ATIs] were evaluated in serial serum samples drawn during IFX induction to facilitate a population-based IFX PK analysis. The AnsrTM IFX assay [Prometheus Inc., San Diego, CA] was used to determine serum IFX and ATI concentrations.13,14 2.4. Pharmacokinetic modeling To ensure the validity of the PK model utilized in the study, summary PK parameters were generated for IFX using a pooled cohort of n = 51 inflammatory bowel disease [IBD] patients [PK cohort] with sequential sampling [Table 1]. Infliximab concentration time data were fit using NONMEM 7 version 2.0 [Icon Development Solutions, Dublin Ireland] with the first-order conditional estimation [FOCE] method.15 The log transform both-sides approach was implemented, and observations that were below the limit of assay quantification were included using the M3 method.16 Standard model-building methods were used, and models were evaluated with standard goodness-of-fit assessments.17 The effects of covariates were first evaluated graphically using Xpose4,18 then evaluated serially in the model. The likelihood ratio test was used to assess nested models. Covariate acceptance was set to p < 0.005 during initial evaluations and at p < 0.001 for backwards elimination and development of the final model. Model evaluation included assessment of parameter precision through standard errors of the estimates, diagnostic goodness-of-fit plots, and a visual predictive check.19 Parameter shrinkage was also evaluated.20 Table 1. Baseline characteristics of the acute UC cohort [n = 36] and the pooled IBD cohort [n = 51] used to validate the PK model [PK cohort]. Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Continuous data are presented as median [min–max]. Where no range is provided, variables represent raw numbers. Mayo score data reported for PK cohort [n=51] is derived from UC patients within this cohort. View Large Table 1. Baseline characteristics of the acute UC cohort [n = 36] and the pooled IBD cohort [n = 51] used to validate the PK model [PK cohort]. Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Acute UC cohort [n = 36] PK cohort [n = 51] Diagnosis UC 36 42 CD 0 9 Age at diagnosis [years] 28.0 [11.6–64.9] 26 [9–65] Gender Male 17 20 Female 19 31 Disease duration [years] 2.89 [0.10–24.00] 4.0 [0–34.0] Mayo score 11 [8–12] 11 [8–12] Weight [kg] 61.0 [44.0–104.0] 61.0 [44.0–104.0] Infliximab dose [mg] 300 [250–500] 300 [250–500] Concomitant thiopurine Yes 4 6 No 32 45 Serum albumin [g/L] 33 [24–48] 34 [24–48] C-reactive protein [mg/L] 33 [1–240] 31 [1–240] Serum immunoglobulin G [g/L] 9 [5–14] 9 [5–16] Continuous data are presented as median [min–max]. Where no range is provided, variables represent raw numbers. Mayo score data reported for PK cohort [n=51] is derived from UC patients within this cohort. View Large 2.5. Study endpoints Evaluation of clinical outcomes was confined to the acute UC cohort [n = 36]. The clinical response was documented at Week 14 [induction therapy outcome] and defined as the impression of the treating physician of a clinical response and the continued utilization of IFX therapy post induction. Corticosteroid-free remission rates were documented at Week 54 [maintenance therapy outcome]. Corticosteroid-free remission was defined as a Mayo score of 0 and the absence of corticosteroid treatment. Infliximab PK during induction and maintenance therapy and covariates associated with drug clearance were evaluated. Infliximab Day 1 induction PK parameters, including effective terminal T1/2 and drug clearance were quantified in the acute UC cohort [n = 36] and their association with induction and maintenance therapy outcomes evaluated. 2.6. Statistical analysis Continuous variables are presented as medians and ranges. Comparisons of differences between groups were assessed by the analysis of variance [ANOVA] or the Kruskal–Wallis ANOVA on ranks as appropriate. Statistical analysis was performed by using SAS [version 9.1.2; SAS Institute, Cary, North Carolina, USA]. 3. Results 3.1. Baseline demographics The baseline characteristics of the acute UC cohort [n = 36] and of the PK cohort [n = 51] are shown in Table 1. For the acute UC cohort [n = 36], the median Mayo score in the study cohort was 11 [range 8–12], with the median corticosteroid dose [PO/IV] at study entry being 50 mg prednisone equivalents. The median endoscopic Mayo score at study entry was 3 [range 2–3]. Of the 36 patients in the acute UC cohort, 33 [92%] had extensive colitis, with the remainder having left-sided colitis. The serum albumin concentration (median [range]) was 33 g/L [24–48]. The median baseline serum CRP concentration was 33 mg/L [range, 1–240]. Of the 36 patients, 9 [25%] required a colectomy during follow-up. 3.2. Induction infliximab pharmacokinetics The final PK model parameters derived from 51 patients [PK cohort] are described in Supplementary Table 1. Because IFX PK are described using a two-compartment model, three different T1/2 values can be computed: the alpha T1/2, which reflects the duration of the initial fast fall-off of IFX after the end of infusion, the beta T1/2, which reflects the slower fall-off of IFX, and an effective T1/2, which combines the two prior values and reflects the contribution of each phase [fast and slow fall-off]. Thus the effective T1/2 provides a more clinically relevant description of the duration of time that IFX will remain measurable after an infusion. The estimated effective IFX T1/2 (median [range]) was 8.42 [3.91–22.03] days, with alpha and beta T1/2 (median [range]) estimates of 2.48 [1.19–3.76] days and 15.33 [7.81–52.48] days, respectively [Figure 1A]. The estimated IFX clearance (median [range]) was 0.50 [0.19–1.41] L/day [Figure 1B]. Induction ATIs were demonstrated in only four subjects [11%] in the study cohort. There was a relationship between serum albumin concentration and induction IFX PK, with a shorter effective IFX T1/2 [p = 0.029] and increased IFX clearance [p = 0.012] in individuals with a low serum albumin concentration [of <35 g/L versus ≥35 g/L] [Figure 2A and B]. Linear regression models demonstrated a significant inverse association between serum albumin concentration and IFX clearance. A significant association between CRP concentration and IFX clearance was also demonstrated using linear regression [Supplementary Figure 1A and B]. Time from initiation of IFX therapy was inversely associated with IFX clearance. Clearance was highest during the induction phase of therapy; in individuals who avoided colectomy, IFX clearance appeared to slow down over time [Figure 3]. The inverse relationship between time on therapy and IFX drug clearance was reversed in the presence of ATIs, with IFX clearance increasing over time in this subgroup of patients [Supplementary Figure 2]. Additional covariates identified as associated with IFX clearance were the presence of ATIs, weight, inter-compartmental clearance and central and peripheral volumes of distribution [Supplementary Table 1]. Due to the small number of patients receiving concomitant immunomodulators, their impact on induction IFX PK could not be assessed. Figure 1. View largeDownload slide Infliximab induction pharmacokinetic [PK] parameters in the acute UC cohort [n = 36 subjects]. Figure 1. View largeDownload slide Infliximab induction pharmacokinetic [PK] parameters in the acute UC cohort [n = 36 subjects]. Figure 2. View largeDownload slide Association between infliximab [IFX] pharmacokinetic [PK] parameters and serum albumin concentration in the acute UC cohort [n = 36 subjects]. Figure 2. View largeDownload slide Association between infliximab [IFX] pharmacokinetic [PK] parameters and serum albumin concentration in the acute UC cohort [n = 36 subjects]. Figure 3. View largeDownload slide Infliximab [IFX] clearance over time in the acute UC cohort [n = 36 subjects] by colectomy status. Figure 3. View largeDownload slide Infliximab [IFX] clearance over time in the acute UC cohort [n = 36 subjects] by colectomy status. 3.3. Association between infliximab pharmacokinetics and outcome of induction therapy The Week 14 clinical response rate was 78% [28/36]. Induction IFX PK parameters were associated with the outcome of induction therapy. A longer effective IFX T1/2 [p = 0.005] and reduced IFX clearance [p = 0.002] were observed when comparing induction responders with subjects who failed to achieve an induction response, respectively [Figure 4A and B]. There was a non-significant trend toward higher Weeks 2 and 6 trough IFX levels in subjects who did not require a colectomy, compared with those who proceeded to colectomy [Supplementary Figure 3]. A representative example of a study subject exhibiting rapid IFX clearance and induction failure is shown in Supplementary Figure 4. Figure 4. View largeDownload slide Induction pharmacokinetic [PK] parameters according to induction therapy outcome in the acute UC cohort [n = 36 subjects]. Figure 4. View largeDownload slide Induction pharmacokinetic [PK] parameters according to induction therapy outcome in the acute UC cohort [n = 36 subjects]. 3.4. Association between infliximab pharmacokinetics and outcome of maintenance therapy The Week 54 corticosteroid-free remission rate was 53% [19/36]. Induction IFX PK were associated with long-term therapy outcome, with a significantly longer IFX T1/2 [p = 0.007] and lower IFX clearance [p = 0.009] in individuals who achieved compared with those who failed to achieve corticosteroid-free remission at Week 54 [Figure 5A and B]. There was a trend toward increasing IFX T1/2 and reducing IFX clearance, moving from the induction failure group who did not proceed to maintenance therapy, through the induction responder group who failed maintenance therapy, to the induction responder group who remained in remission at one year. IFX T1/2 was significantly longer and IFX clearance lower in induction responders who remained in remission compared with induction failures who did not receive maintenance therapy [p = 0.002 and p = 0.003, respectively] [Figure 5C and D]. Of the 36 patients in the acute UC cohort, 6 [17%] were found to be ATI positive during study follow-up. Figure 5. View largeDownload slide Relationship between induction infliximab [IFX] pharmacokinetic [PK] parameters and corticosteroid-free remission at Week 54 and combined induction and maintenance therapy outcomes in the acute UC cohort [n = 36 subjects]. Figure 5. View largeDownload slide Relationship between induction infliximab [IFX] pharmacokinetic [PK] parameters and corticosteroid-free remission at Week 54 and combined induction and maintenance therapy outcomes in the acute UC cohort [n = 36 subjects]. 4. Discussion Although IFX is an important component of the therapeutic armament in acute UC, outcomes from clinical trials have been variable.1,21,22 Differences in the trough IFX concentrations when comparing UC and CD,7,8 and the lesser therapy response rates in severe UC patient populations, suggest that IFX PK may be an important variable contributing to therapy failure.22 We studied the PK of IFX in a cohort of patients with corticosteroid-refractory acute UC. Of the 36 patients in the study cohort, 33 were hospitalized. We evaluated whether induction IFX PK parameters were associated with short- and long-term therapy outcomes. We confirmed that there was a significantly increased IFX clearance and shorter IFX T1/2 in our acute UC cohort, compared with previous estimates derived from ambulatory cohorts with moderately active UC. We also demonstrated a relationship between induction IFX PK parameters and therapy outcome, with decreased IFX T1/2 and increased IFX clearance associated with both induction and maintenance therapy failure. Population-based PK analyses using data from the ACT 1 and 2 randomized control trials generated an estimated IFX T1/2 in UC of 14 days.6 ACT 1 and 2 included UC patients with moderately severe disease (median Mayo score of 8 [range 4–12], 56% utilizing concomitant corticosteroids).1 A similar population-based PK analysis using data from the ACCENT 1 randomized controlled trial, which included patients with moderately active CD, generated an estimated IFX T1/2 of 12.4 days.2,5 The cohort of patients evaluated in this report had significantly more severe disease [median Mayo score 11; 33 of 36 hospitalized; median corticosteroid dose at study entry 50 mg prednisone equivalents] than those evaluated in the ACT 1 and 2 trials. We demonstrated IFX PK to differ significantly in our cohort compared with previously reported IFX PK.5,6 The effective IFX T1/2 estimate in our cohort was 8.42 days. Our data are in concordance with those from Ungar et al., which demonstrated Day 14 trough IFX levels to be significantly lower in patients with acute severe UC compared with in patients with moderately severe UC.9 The shorter IFX T1/2 observed in more severe UC cohorts is likely reflective of an increased inflammatory disease burden, which is increasingly being recognised as a factor that influences IFX clearance and consequently drug T1/2. The PK and pharmacodynamics of therapeutic monoclonal antibodies are complex and depend on antibody structure, the characteristics of the target antigen, patient factors, and disease-related factors. Pharmacokinetic–pharmacodynamic factors are interrelated and play an important role in understanding the association between drug concentration and therapeutic response. While determinants of IFX PK remain poorly understood, a number of factors have been shown to increase IFX clearance, including inflammatory burden of disease [high baseline TNF], low albumin, high body weight, the presence of ATIs, and lack of concurrent immunomodulator use.23 Substantiating previous data, we demonstrated that decreased serum albumin and increased CRP concentration were associated with increased IFX clearance and decreased drug T1/2.24,25 These associations support the hypothesis that inflammatory burden is an important determinant of IFX PK in IBD cohorts. The concept of inflammatory burden refers to intestinal ‘TNF antigen load’, which if significantly elevated, may result in increased drug clearance by antigen-dependant pathways. In addition to its association with inflammatory burden, a decreased serum albumin concentration may be a manifestation of a protein-losing enteropathy, which could represent an additional mechanism of increased IFX clearance in moderate-to-severe UC. Support for this hypothesis was provided by a report of elevated fecal IFX concentrations in subjects with acute severe UC failing induction therapy.26 Immunogenicity is an issue associated with the use of therapeutic monoclonal antibodies. Development of ATIs increases drug clearance by the formation of immune complexes, which accelerate drug clearance by the reticuloendothelial system, or impair binding to the target antigen.23 The presence of ATIs in the maintenance phase of therapy has previously been shown to increase IFX clearance in UC and CD5,6; however, little is known about the influence of ATIs on IFX PK during induction therapy. ATI estimations in this report were performed using a homogeneous mobility shift assay [Prometheus Laboratories, San Diego, CA].27 In our cohort, ATI formation was uncommon during induction, with only 11% of subjects found to be ATI positive. The study PK model demonstrated ATIs to increase drug clearance significantly. With the initial appearance of ATIs, the effect on clearance is minor [generally due to low titers], but this impact increases over time and is particularly relevant in the maintenance phase of therapy. The prevalence of induction ATIs in our report differed from that in the two other studies that examined induction ATI rates in patients with acute UC.9,27 This may be explained by a number of factors, including the differences in the assays utilized to detect ATIs [although all assays were drug tolerant], relatively small patient cohorts, study population heterogeneity, and differing time points at which induction ATIs were assessed. Concurrent use of immunomodulators has been shown to increase the serum concentration of IFX and to decrease IFX clearance.28–30 Only 4 of the 36 patients in the acute UC cohort studied were receiving concurrent immunomodulators; therefore, we could not assess the effect of immunomodulators on IFX clearance in this study. An important finding of the study was the association between induction IFX PK parameters and the outcome of induction and maintenance therapy. Accelerated IFX clearance during induction with a shorter IFX T1/2was associated with reduced induction [Week 14] clinical response and maintenance [Week 54] corticosteroid-free remission rates. These data are in concordance with a report from Brandse et al., which demonstrated lower Week 6 serum IFX concentrations in primary non-responders compared with in responders in a cohort with moderate-to-severe UC receiving IFX induction.27 The data we report provide mechanistic information that suggest that accelerated IFX dosing may improve the outcome of corticosteroid-refractory acute UC; however, it is important to emphasize that the data are associative rather than causative. Accelerated IFX clearance may be a mechanism of therapy failure in corticosteroid-refractory acute UC. It is also possible, however, that adverse induction IFX PK parameters are merely a marker of severe disease and consequently of patients likely to fail IFX therapy irrespective of the induction schedule utilized. Three studies have directly examined the clinical outcome of accelerated IFX dosing in acute UC with contrasting results. Gibson et al. performed a retrospective evaluation of n = 50 hospitalized patients with corticosteroid-refractory acute severe UC treated with accelerated [n = 15] and standard [n = 35] IFX induction regimens. Disease severity at baseline was similar in the accelerated dosing subgroup to that in the standard dosing subgroup. Significantly reduced 3- and 6-month colectomy rates were observed in the accelerated dosing subgroup, compared with the standard induction dosing subgroup.31 Choy et al. provided further support for this therapeutic approach in an abstract publication that compared the outcome of accelerated and standard IFX dosing in corticosteroid-refractory acute severe UC. The 3- and 12-month colectomy rates for the accelerated and standard dosing groups were similar, despite individuals receiving accelerated IFX dosing having more severe baseline disease.32 In contrast, data presented in abstract form by Govani et al. did not demonstrate a benefit of accelerated IFX dosing in a cohort [n = 57] of hospitalized patients with acute severe UC.33 The available clinical data describing the outcome of accelerated compared with standard IFX dosing for acute corticosteroid-refractory UC has limitations. It is retrospective in nature and involves small cohorts. In addition, in the reports by Choy et al. and Govani et al., the accelerated dosing group had more severe baseline disease than the standard dosing group, making comparison of outcomes between these groups difficult.32,33 It is our view that, the IFX PK data we report, along with the available observational clinical data, support the use of accelerated IFX induction in selected patients with corticosteroid-refractory acute severe UC. Prospective trials are required in order to definitively examine the impact on therapy outcome of accelerated compared with conventional IFX dosing on this UC patient subgroup. In summary, we have demonstrated that patients with corticosteroid-refractory acute UC have increased IFX clearance and a shorter IFX T1/2 than previously studied moderately active outpatient UC cohorts. Induction IFX PK parameters are associated with induction and maintenance therapy outcomes. Decreased serum albumin and increased CRP concentrations are associated with accelerated IFX clearance during induction, substantiating inflammatory disease burden as an important determinant of IFX PK. These mechanistic data support the use of accelerated IFX induction regimens in patients with corticosteroid-refractory acute UC who are failing to achieve an adequate therapeutic response to conventional dosing schedules. Prospective trials in UC are required in order to formally evaluate the efficacy and safety of accelerated versus conventional IFX dosing regimens, and to define patient subgroups most likely to benefit from these treatment strategies. Funding DK is a recipient of a CIHR / Canadian Association of Gastroenterology [CAG] / Abbvie IBD Fellowship. MSS is supported by the Gale and Graham Wright Chair in Digestive Diseases at Mount Sinai Hospital, Toronto. Conflict of Interest The authors have no conflicts to disclose. The authors would like to disclose the support provided by Prometheus Laboratories, San Diego, CA for this study by way of their performance of infliximab therapeutic drug monitoring assessments. Author Contributions D.K.: patient recruitment, data collection, study design, data analysis, writing up of manuscript; S.M.: patient recruitment, data collection and review of manuscript; D.R.M.: study design, data analysis, writing up of manuscript; M.S.S.: study design, data analysis, writing up of manuscript. Supplementary Data Supplementary data are available at ECCO-JCC online. Acknowledgments The authors would like to acknowledge the pivotal contribution of the late Dr Gordon R Greenberg to the conception, design and conduct of this study. They would also like to acknowledge his invaluable contribution to the analysis and interpretation of data contained within the study. We would also like to acknowledge the significant contribution of Anna Iacono to the conduct of this study. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Crohn's and ColitisOxford University Press

Published: Apr 6, 2018

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