Sa1251 Infliximab Trough Levels and Antibodies: Relationship With Infusion Reaction, Immunomodulators and Biological Parameters

Abstract

Background: Adalimumab (ADA), a monoclonal antibody against TNFα is effective therapy for inflammatory bowel diseases (IBD: ulcerative colitis (UC) and Crohn's 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.