BackgroundInfliximab is a monoclonal antibody approved for the treatment of inflammatory diseases. The best approach in adjusting the dose of infliximab because of the high interindividual variability in serum concentrations is with a Bayesian approach.PurposeOur aim was to estimate the precision and accuracy of five pharmacokinetic models (PopPKmodel) in patients with inflammatory bowel disease.Material and methodsAn observational retrospective study was designed. Patients with ulcerative colitis or Crohn’s disease treated with infliximab during 2014 were included. Trough blood samples for determining infliximab were drawn. Five PopPKmodels were implemented in NONMEM: PopPK in ulcerative colitis and Crohn’s disease. The Infliximab concentrations were estimated from five models at the sample times, through the empirical Bayesian of estimates (EBEs) of the pharmacokinetic parameters. To validate these models, bias of estimated concentrations were calculated as the mean residual predictive error (MRPE) and the precision was calculated as the root mean square predictive error (RMSPE) in our population.ResultsTwo hundred and seventy-three serum infliximab concentrations from 160 patients (54% males and 46% females) were included. The mean age was 36 years (CI 95%: 31 to 41), weight 73.1 kg (CI 95%: 71.1 to 75.2) and 3.92 mg/dL (CI 95%: 3.86 to 3.98) baseline serum albumin concentration. 62.5% of patients were diagnosed with Crohn’s disease and 36.3% for ulcerative colitis. The mean trough serum concentration of infliximab was 4.1 mg/L (CI 95%: 3.6 to 4.6). 68.1% of patients were treated with infliximab and 31.9% with biosimilar. Bias of estimated concentrations (MRPE) and precision (RMSPE):Abstract 4CPS-165 Table 1 Accuracy (mean, CI 95% ) Precision (mean, CI 95% ) Model 1 36.8 (92–18.3) 468 (65–1001) Model 2 54. 1 (142.5–34.2) 752 (137–1642) Model 3 442 (1213–328) 6558 (1345–14462) Model 4 17 (51–15) 285 (66–637) Model 5 73 (197–50) 1054 (197–2305) ConclusionIn our study, neither PopPKmodels overestimate infliximab concentrations in the population, although Model 4 was better, (i.e. closer to zero) in terms of bias and accuracy.Reference and/or Acknowledgements1. Fasanmade, et al. 2009: Model 1;2. Fasanmade, et al. 2011: Model 2; Buurman y col, 2015: Model 3; Dotan y col, 2014: Model 4 and Brandse y col, 2017: Model 5.No conflict of interest
Background Therapeutic drug monitoring (TDM) postinduction of vedolizumab (VDZ) could have relationship with long-term outcome of inflammatory bowel disease (IBD) patients. However, clinical utility of TDM during maintenance VDZ therapy remains unclear. To examine the association of induction and maintenance vedolizumab though levels (VTL) with clinical and biochemical long-term outcome in IBD patients. Methods We performed a retrospective cohort study, including all consecutive IBD patients of our centre on VDZ treatment who had VTL and anti-vedolizumab antibodies (AVA) measured during induction and maintenance therapy. All patients had received a minimum of 6 weeks therapy following standard induction (0, 2, 6 ± 10 week dosing. Clinical response and remission were defined by Partial Mayo Score (PMS, UC) or Harvey Bradshaw Index (HBI, CD) and were assessed at week 52.Biochemical remission was defined as CRP < 0.5 g/dl and faecal biomarker remission as faecal calprotectin (FC) < 250 µg/g. Measurement of VTL and AVA was performed by ELISA assays(Vedolizumab-TheraDiag(R) with a detection limit for VTL of 2 μg/ml and measurement range of 2–60 μg/ml. Results In total, 34 patients were included (55.9% UC; 44.1% CD, 50% women). Median age was 52.76(17–83) and mean disease duration was 8 ± 7.2 years. Median baseline HBI was 6(0–12) and PMS was 5(3–7). FC and CRP measured before first dose of VDZ were 1425 ± 1189 μg/g and 2.1 ± 2.4 mg/dl. A total of 14 patients (41.2%) were naïve for biologic therapy. Only three patients (8.8%) were receiving a concomitant immunomodulator. Clinical response to induction phase was reported in 76%. Clinical remission, clinical response, biochemical remission and faecal biomarker remission were present in 30% (9/29), 41.4% (12/29), 40.9% (9/22) and 35% (7/20), respectively, at week 52. Thirteen patients (13/26, 50%) needed dose escalation at week 52. Twenty-six patients (78.8%) were persistent in VDZ therapy at the end of the study. The median level of VDZ at weeks 6 and 24 were 16.13 ± 7.06 μg/ml and 9.6 ± 6.7 μg/ml. Comparing patients with and without clinical response or remission to VDZ at week 52 no significant difference in VTL was found at Week 6 (16.27 vs. 15.46 μg/ml, p = 0.8) and week 24 (7.6 vs. 12.7 μg/ml, p = 0.1). No difference was observed in VTL in patients in biochemical remission (week 6: 23.6 vs. 15.7 μg/ml, p = 0.2; week 24: 10.3 vs. 10.2 μg/ml, p = 0.9) or with faecal biomarker remission (week 6: week 6: 25.5 vs. 16.2 μg/ml, p = 0.1; week 24: 10.7 vs. 8.2 μg/ml, p = 0.6) at week 52. No patient developed antibodies. Conclusion In this real-world study of IBD patients receiving VDZ, early induction or maintenance VTL are not associated with long-term outcome.
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