Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection

Alexander Eser, Walter Reinisch, Stefan Schreiber, Tariq Ahmad, Suliman Boulos, Diane R Mould, Alexander Eser, Walter Reinisch, Stefan Schreiber, Tariq Ahmad, Suliman Boulos, Diane R Mould

Abstract

Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.

Keywords: antidrug antibody; drug clearance; infliximab; pharmacokinetics.

Conflict of interest statement

A.E., W.R., S.S., T.A., and D.R.M. have no disclosures related to the submitted work. S.B. was employed by CELLTRION Healthcare Co., Ltd (Incheon, Republic of Korea) during preparation of this article and is currently employed at the Shaare Zedek Medical Center, Israel.

© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Effects of different patient factors on infliximab clearance: body weight (A), ADA concentration (B), albumin (C), CRP (D), and glucose (E). In all panels, the open blue circles represent the individual parameter values, the solid red line is the bootstrap median of the covariate effect, and the shaded gray area is the 90% bootstrap confidence interval of the covariate effect. ADA, antidrug antibody; CRP, C‐reactive protein.
Figure 2
Figure 2
Effects of patient sex (A) and concomitant immunosuppressant therapy (B) on infliximab clearance. In these panels, the solid line in the middle represents the bootstrap median, the lower edge of the box is the lower 25th percentile, the upper edge of the box is the upper 75th percentile, the whiskers represent the lower 5th and upper 95th percentiles, and the symbols above the whisker are outliers.
Figure 3
Figure 3
Effects of baseline infliximab clearance (A) and body weight (B) on the probability of ADA formation. ADA, antidrug antibody; CI, confidence interval.

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