Lior Yahav

Patient Factors That Increase Infliximab Clearance and Shorten Half-life in Inflammatory Bowel Disease: A Population Pharmacokinetic Study

Background:Infliximab (IFX) is effective therapy for ulcerative colitis and Crohns disease, but it may be associated with side effects and loss of response. One loss of response mechanism is increased IFX clearance (IFX-CL), resulting in short half-life and decreased troughs. Methods:Patients were recruited, and relevant demographic, clinical, and laboratory data were recorded. IFX serum concentrations and antibodies against IFX (ATI) were measured for therapeutic drug monitoring and modeled using NONMEM. Results:There were 169 IFX concentrations (Crohns disease = 73, ulcerative colitis = 92, and diagnosis undetermined = 4). Patient factors significantly associated with high IFX-CL were low albumin, high body weight, and the presence of ATI (P ⩽ 0.001). Disease type did not affect IFX-CL. The typical IFX-CL was 0.381 L/d. ATI formation was associated with a 259% increase in IFX-CL. The estimated median IFX effective half-life was 5.6 ± 2.4 days. Patients with low weight are more likely to have low troughs because IFX CL is not linearly related to weight, but IFX dosing is weight-based (in mg/kg). Simulations investigating alternative dose strategies suggested that more reliably measurable concentrations over the dose interval were achieved when the dose interval was shortened than by increasing administered dose. Conclusions:IFX-CL is significantly influenced by patient factors, specifically, albumin, body weight, and ATI. There should be a decreasing IFX dose interval strategy, particularly for low albumin patients. Higher starting doses may benefit low body weight patients. Pharmacokinetic models and therapeutic drug monitoring may ensure that patients maintain measurable concentrations throughout dose intervals. Individualized dosing may improve outcomes for IFX-treated patients with Crohns disease and ulcerative colitis.

Pouch Inflammation Is Associated With a Decrease in Specific Bacterial Taxa

BACKGROUND & AIMS Pouchitis is a common long-term complication in patients with ulcerative colitis (UC) undergoing proctocolectomy with ileal pouch-anal anastomosis. Because the inflammation occurs in a previously normal small bowel, studies of this process might provide information about the development of Crohns disease. Little is known about the intestinal microbiome of patients with pouchitis. We investigated whether specific bacterial populations correlate with the pouch disease phenotype and inflammatory activity. METHODS We performed a prospective study of patients with UC who underwent pouch surgery (N = 131) from 1981 through 2012 and were followed at Tel Aviv Medical Center. Patients were assigned to groups based on their degree and type of pouch inflammation. Patients with familial adenomatous polyposis after pouch surgery (n = 9), individuals with intact colons undergoing surveillance colonoscopy (n = 10), and patients with UC who did not undergo surgery (n = 9) served as controls. We collected demographic and disease activity data (based on the Pouchitis Disease Activity Index) and measured levels of C-reactive protein. Fecal samples were collected, levels of calprotectin were measured, and microbiota were analyzed by 16S ribosomal RNA gene amplicon pyrosequencing. RESULTS Increased proportions of the Fusobacteriaceae family correlated with increased disease activity and levels of C-reactive protein in patients with UC who underwent pouch surgery. In contrast, proportions of Faecalibacterium were reduced in patients with pouchitis vs controls; there was a negative correlation between proportion of Faecalibacterium and level of C-reactive protein. There was an association between antibiotic treatment, but not biologic or immunomodulatory therapy, with reduced proportions of 11 genera and with increased proportions of Enterococcus and Enterobacteriaceae. CONCLUSIONS Reductions in protective bacteria and increases in inflammatory bacteria are associated with pouch inflammation in patients with UC who underwent pouch surgery. The finding that antibiotics exacerbate dysbiosis indicates that these drugs might not provide long-term benefit for patients with pouchitis. Additional studies of this form of dysbiosis could provide information about the pathogenesis of Crohns disease.

Antibodies against glycoprotein 2 are novel markers of intestinal inflammation in patients with an ileal pouch

BACKGROUND AND AIMS The Crohns disease (CD)-specific pancreatic auto-antibodies (PAB), have been recently identified to target glycoprotein 2 (GP2). Pouchitis is an inflammation of the small bowel developing in up to 60% of ulcerative colitis patients undergoing proctocolectomy and ileal pouch anal anastomosis. Occurrence of CD-specific antibodies was reported to be a predictor of pouchitis. We aimed to assess the prevalence of anti-GP2 antibodies (anti-GP2) in the serum and feces of pouch patients and to correlate them with clinical parameters. Furthermore, we examined mucosal expression of the GP2 protein in the pouch. METHODS Pouch patients were prospectively recruited and checked for clinical, endoscopic, and laboratory markers of inflammation. IgG and IgA anti-GP2 levels in serum and fecal samples were determined using ELISA. GP2 protein was assessed by immunohistochemistry. RESULTS Anti-GP2 was elevated in both serum and fecal samples of patients with inflamed compared to those with non-inflamed pouches and patients with familial-adenomatous polyposis after surgery (p<0.05, respectively). Moreover, patients with CD-like complications exhibited significantly higher anti-GP2 titers than those without CD-like complications (p≤0.01). High levels of anti-GP2 correlated with more frequent bowel movements per day and with the presence of at least one anti-glycan antibody (p≤0.05). GP2 itself was more abundant in the mucosa of patients with chronic pouchitis. CONCLUSIONS Anti-GP2 exists in the serum and feces of pouch patients and correlates with pouch inflammation, and presence of other serological markers. Thus, anti-GP2 may contribute to better stratification of pouchitis, more-so when the inflammation exhibits CD-like complications.

Sa1197 Ulcerative Colitis Patients After Pouch Operation Are Serologically More Comparable to Crohn's Disease Patients

characteristic (ROC) curves. The strength of relationship was evaluated according to conventional thresholds whereby 0.2, 0.5, and 0.8 indicate small, moderate, and large degrees of responsiveness, respectively.1 Results: Among 121 patients, 29 were clinically unchanged and 92 were changed (Table 1). Between weeks 0 and 6 or 10, the effect sizes and Guyatts responsiveness statistics (95% confidence intervals [CIs]) based on mean scores for the MMCS, MBS, and UCEIS were 0.49 (0.28, 0.71), 0.49 (0.28, 0.71), and 0.58 (0.36, 0.81) and 0.32 (0.11, 0.53), 0.33 (0.12, 0.54), and 0.47 (0.25, 0.69), respectively. The corresponding estimates (95% CI) for the areas under the ROC curves were 0.66 (0.55, 0.78), 0.65 (0.54, 0.77), and 0.68 (0.58, 0.79) The ROC curves are displayed in Figure 1. Conclusion: Although the UCEIS had greater numerical values, the MMCS, MBS, and UCEIS displayed similar, small-to-moderate, responsiveness for the assessment of UC disease activity. These results have important implications for sample size in early drug development. References 1. Husted JA, Cook RJ, Farewell VT, Gladman DD. Methods for assessing responsiveness: a critical review and recommendations. J Clin Epidemiol. 2000 May;53(5):459-68. Table 1. Score changes between 0 and 6/10weeks in clinically changed and unchanged groups

Sa1250 Population Pharmacokinetic Evaluation of Adlimumab Reveals Patient Factors That Increase Adalimumab Clearance and Shorten Half-Life in Inflammatory Bowel Disease Patients

Background: Adalimumab (ADA), a monoclonal antibody against TNFα is effective therapy for inflammatory bowel diseases (IBD: ulcerative colitis (UC) and Crohns disease (CD)). Loss of response to ADA may be the consequence of increased ADA clearance (CL), resulting in short half-life (t1/2) and decreased troughs. Studies evaluating ADA pharmacokinetics (PK) in IBD are scarce. Aim: To generate a preliminary PK model for ADA and to investigate factors affecting ADA PK variability in IBD. Methods: IBD patients were prospectively recruited; ADA serum concentrations as well as antibodies toward ADA (ATA) were measured by ELISA (Immundiagnostik AG) during therapeutic drug monitoring (TDM). Demographic, clinical and laboratory data were recorded. ADA data were evaluated using population modeling (NonmemVersion 7.2 Icon Development). Standard PKmodel building approaches and performance evaluations were used. The absorption rate constant (Ka) was fixed to 0.02 hr-1 (consistent with the product label). Apparent CL/bioavailability (F), volume of distribution and between-patient variability for CL/F were estimated. Results: ADA concentrations (n=87) from 63 patients (CD:56, UC:7) were evaluated. Baseline (mean ± SD) demographics were: weight 60.5±23.9 kg, age 36.4±12.1 years, males: 33, BMI 21.0±7.8 kg/cm2, CRP 19.7±28.4 mg/L, albumin 4.0±0.54 g/dL. Positive ATA at first sampling were present in 9 patients, and further developed in 2. Moderate/severe disease activity was detected in 17/2 subjects, respectively. ADA as second line treatment was given to 37/63 (58.7%) patients. Dosage at sampling was 40/2 mg/weeks for 54 (85.7%), and 80/2 for 7 (11.1%) subjects. PK data were best described using a one compartment model with linear elimination. Parameter precision was good ( 0.05. Typical (ATA negative, weight 70 kg, ALB 4 g/dL) CL/F was 0.0124 L/hr. ATA formation was associated with a nearly 5 fold increase in ADA CL/F. Conclusions: ADA CL/F is significantly influenced by patient factors. ATA, concomitant use of antibiotics and corticosteroids, higher ADA doses and ADA as second line of therapy increase CL/F. The highly variable t1/2 suggests that interval shortening rather than increased doses may ensure higher exposure and increased troughs. The high between-patient variability suggests that additional factors affect troughs and that individualized, PK-guided rather than fixed dosing, may improve IBD patient outcomes.