The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Abstract

Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a onecompartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

“…18 Patients with UC had a 45.8% faster clearance, in line with a previous pharmacokinetic study. 19 Patients receiving azathioprine co treatment had a 15.1% decrease in infliximab clearance, which confirms previous reports on the effects of combotherapy. 20,21 This result may be explained by the immunosuppressive effects of azathioprine, which decrease the risk of immunization to infliximab and the activity of the disease, and consequently the target-mediated elimination of infliximab.…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…[98] The retention of rituximab may explain, at least in part, the differences in values of pharmacokinetic parameters between follicular lymphoma and RA on one hand, and DLBCL in the other hand. Of note, the type of disease was associated with volume variations of: -ganitumab [146] , volume of distribution being higher in pancreatic cancer patients than others; -infliximab [107] , volume of distribution being increased by 25% in IBD compared than in other diseases (spondylarthropathies, RA). Apparent increase in volume of distribution in IBD is associated with an increase in T½R.…”

“…The 4 studies of anticancer mAbs that reported different mAb clearances among types of tumour did not investigate pathophysiological reasons of such differences. Besides, in inflammatory bowel diseases (IBD), 2 publications reported volumes of distribution and clearances of infliximab [107] and of vedolizumab [70] slightly superior for ulcerative colitis than for Crohn's disease, but again, there is no evidence of differences in antigen mass due to diseases. However, the intrinsic catabolism rate of a given mAb might be modified between diseases.…”

“…In 7 publications, the type or subtype of disease was associated with differences in pharmacokinetic parameters. [67,70,107,136,[144][145][146] One of possible reasons of such differences are differences in amount and turnover (RT, ksyn, kdeg, see section 4.2), and localization (and therefore the accessibility by mAb) of antigenic targets. The 4 studies of anticancer mAbs that reported different mAb clearances among types of tumour did not investigate pathophysiological reasons of such differences.…”

Pharmacokinetic Similarity of ABP 710, a Proposed Biosimilar to Infliximab: Results From a Randomized, Single‐Blind, Single‐Dose, Parallel‐Group Study in Healthy Subjects

“…Cross-study comparisons have shown that patients with the inflammatory disease ulcerative colitis had a 45.8% faster clearance of infliximab than healthy volunteers. 3 It has also been shown that C-reactive protein (CRP), a marker of inflammation, is positively correlated with clearance of infliximab. When CRP was used as a time-varying covariate in a PK model in a population of patients with inflammatory bowel disease, results indicated that a CRP of 100 mg/L increased infliximab clearance by 21.6%.…”