Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn's disease

Abstract

Certolizumab pegol (CZP), an anti-tumor necrosis factor a agent, is an effective therapy for Crohn's disease (CD). A population pharmacokinetic (PK) analysis of subcutaneously administered CZP was performed using data from 2157 CD patients from 9 separate studies. The aim was to determine which covariates influence the disposition of CZP. The final CZP population PK model consisted of a baseline, first-order absorption, and 1-compartment disposition. CZP antibodies were treated as a structural model covariate and caused apparent clearance (CL/F) to increase from 0.685 to 2.74 L/day. Body surface area (BSA) influenced both CL/F and apparent volume of distribution (V/F) in a linear fashion; both parameters increased by more than 53% and 49%, respectively, across the range of BSA measurements in the data. Albumin influenced CZP CL/F in a nonlinear fashion; CL/F decreased from 1.05 to 0.613 L/day with increasing albumin concentrations in antibody-negative patients. C-reactive protein (CRP) had a borderline influence and CL/F increased by more than 20% across the range of CRP measurements in the data set. Race had a minor influence on V/F. The determined covariates' impact on CZP disposition may be of clinical utility in CZP therapy of CD patients when the PK/pharmacodynamic relationship becomes available.

Improving The Sensitivity and Specificity of A Bioanalytical Assay for The Measurement of Certolizumab Pegol

“…Crucially, the new assay validated using the MSD system exhibited a more than tenfold increase in sensitivity compared with the previous ELISA [23] with improved selectivity for intact CZP as demonstrated by plasma samples from healthy volunteers and patients with rheumatoid arthritis, Crohn's disease and psoriasis. Accuracy and precision met acceptance criteria in both interassay and intra-assay evaluations.…”

“…While the MSD electrochemiluminescence assay utilized several critical reagents similar to those used in the previous ELISA (e.g., TNF-α as a capture reagent) [23], it is important to highlight the key differences between the two assays. The ELISA used a horseradish peroxidase-conjugated anti-human kappa light chain antibody whereas the MSD assay used a biotinylated anti-PEG mAb, revealed with a ruthenium SULFO-TAG™ streptavidin conjugate.…”

“…TNF-α (R&D systems) was chosen as the capture reagent over an anti-idiotype antibody for the new MSD method, to ensure consistency with the previous ELISA method [23] and avoid affinity-related discrepancies in the immunocapture of CZP.…”

“…These samples were tested in triplicate, in two assay runs of both the ELISA and MSD methods. Due to the dissimilar calibration range of the two methods (range of the previous ELISA method: 0.41-1332.0 μg/ml) [23], differing dilutions were required to allow the concentration of the samples to fall within the respective range of the standard curve. The percentage bias, CV and percentage difference between the methods were all required to be ≤20% in order to be considered acceptable.…”

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

“…Th e presence of a low serum albumin may indicate compromised protein status, but it can also be because of infection, burns, fl uid overload, hepatic failure, cancer, or the nephrotic syndrome. Serum albumin has been shown to be a predictive factor related to the pharmacokinetics of anti-TNF therapy-specifi cally infl iximab ( 52 ) and certolizumab pegol ( 53 ). Th e presence of a low serum albumin concentration has been linked to more rapid clearance of anti-TNF agents and poorer clinical outcomes in patients with IBD.…”