Infliximab Pharmacokinetics are Influenced by Intravenous Immunoglobulin Administration in Patients with Kawasaki Disease
Infliximab, a monoclonal antibody directed against tumor necrosis factor-α, is being evaluated as adjunctive therapy to intravenous immunoglobulin (IVIG) for treatment of young children with acute Kawasaki disease (KD).
The aim of this study was to develop a population pharmacokinetic (PopPK) model for infliximab in children with KD, and to evaluate the impact of covariates on infliximab disposition. Specifically, we wanted to investigate the effect of body weight and IVIG administration on PK parameters.
In the current PopPK analysis, 70 subjects with a median (interquartile range) age of 2.9 years (1.3–4.4) were included from two randomized controlled trials. Infliximab concentration–time data were best described by a two-compartment model with first-order elimination using non-linear mixed-effects modeling (NONMEM 7.3).
The clearance, volume of distribution of the central (V1) and peripheral (V2) compartment, and intercompartmental clearance estimates (95% confidence interval) from the PopPK analysis were 0.117 (0.091–0.134) L/day, 0.801 (0.545–0.960) L, 0.962 (0.733–1.759) L, and 0.692 (0.482–1.779) L/day, respectively. Allometric body weight was included on all parameters of the structural model and a covariate analysis revealed that administering infliximab after IVIG, as opposed to before, resulted in a 50% decrease in V2.
Our study shows that the timing of infliximab administration relative to IVIG administration affects the disposition of the monoclonal antibody. These results may have important implications for other monoclonal antibodies administered in combination with IVIG for treating inflammatory diseases.
The authors thank Joan Pancheri, RN, for clinical sample collection, DeeAnna Scherrer for technical assistance, and Emelia Bainto and Nipha Sivilay for database development.
NVC wrote the manuscript; NVC, AHT, and JCB designed the research; NVC, JO, CS, AHT, and JCB performed the research; NVC, JO, CS, BMB, EVC, AHT, and JCB analyzed the data; and JO, CS, BMB, EVC, AHT, and JCB critically revised the manuscript for important intellectual content. All authors approved the final version of the article, including the authorship list.
Compliance with Ethical Standards
No funding was received for any part of the development and publication of the manuscript. The study by Burns et al. was supported by a grant from Centocor, Inc. and the National Institute for Child Health and Human Development, Pediatric Pharmacology Research Unit (PPRU) Network (5U10HD031318). Centocor Inc. performed the determinations of infliximab levels and the assays for anti-infliximab antibodies. The study by Tremoulet et al. was supported in part by an FDA Orphan Drug grant (FD 003514) awarded to JCB, and a Robert Wood Johnson Foundation grant awarded to AHT. Janssen Biotech, the manufacturer of infliximab, provided commercial-grade drug for this study.
Conflict of interest
Niels Vande Casteele has received consultancy fees from Janssen outside of the submitted work. Jun Oyamada, Chisato Shimizu, Brookie M. Best, Edmund V. Capparelli, Adriana H. Tremoulet, and Jane C. Burns have no conflicts of interest to declare.
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