Pharmacokinetics, bioavailability, & bioequivalenceOriginal researchPharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials
Introduction
Infliximab is a recombinant chimeric immunoglobulin (Ig) G1κ monoclonal antibody (MAb) that neutralizes the biological activity of soluble and membrane-bound tumor necrosis factor (TNF)-α. Infliximab is used for the treatment of rheumatoid arthritis,1, 2 ankylosing spondylitis,3 psoriatic arthritis,4 plaque psoriasis,5, 6, 7, luminal8, 9 or fistulizing10, 11 Crohn's disease (CD), and ulcerative colitis12 in adult patients and in the treatment of CD in pediatric patients.13 The use of infliximab to treat these chronic inflammatory diseases should be weighed against the known risks of serious opportunistic infections and the possible association of malignancies with the long-term use of anti–TNF-α therapeutic MAbs.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
The pharmacokinetic (PK) properties of infliximab have been reported in patients with ankylosing spondylitis,16 rheumatoid arthritis,1 inflammatory bowel disease,17 and ulcerative colitis.18 Interindividual variability (IIV) in serum infliximab concentrations has been reported during treatment.1, 16, 17, 18 Although serum infliximab concentrations influence clinical outcomes observed in luminal19 and fistulizing20 CD, rheumatoid arthritis,21 and psoriatic arthritis,22 a literature search identified no detailed population PK analysis has been reported in pediatric and adult patients with luminal CD.
Unlike small-molecule medications, the mechanism of disposition of infliximab and that of other MAbs has not been fully established across age groups. There are indications that, contrary to expectations for small molecules, kidney and liver function within normal ranges may not be directly related to infliximab PK properties.18, 23 Therefore, the established enzyme maturity paradigm24 that explains certain age-related differences (or lack thereof) from neonates to adolescents may not apply to MAbs. Thus, comparing infliximab PK properties between different age groups is necessary.
Obtaining adequate blood samples for determining drug concentrations for a full PK parameter calculation using standard PK methods is usually infeasible in children. Thus, a Bayesian PK approach has been suggested for this situation.25 Even with adequate sampling in each pediatric patient, difficulties in recruiting large numbers of children for study limit the feasibility of performing a standard 2-stage PK analysis. Furthermore, for ethical reasons, pediatric bridging PK studies—especially studies of approved drugs—may not include all of the treatment dosage arms tested in adults. For these reasons, population PK modeling and simulations may be necessary for providing covariate–PK relationships in the pediatric (sometimes in combination with the adult) data.
Different infliximab doses/dosing regimens are required for different diseases.3, 9, 11, 12, 13, 26 Disease- and patient-specific differences may exist for infliximab disposition, and blood concentration requirements for effectiveness may differ among diseases. In particular, covariates affecting infliximab PK have been reported to be different between rheumatoid arthritis1 and ulcerative colitis18 (eg, concurrent administration of immunomodulators had a notable effect on the PK properties of infliximab in rheumatoid arthritis1 but not ulcerative colitis18). Thus, a comparison of PK properties between adult and pediatric patients is needed in patients with the same underlying disease to facilitate the interpretation of the findings of PK analyses.
The present analysis applied population PK techniques to determine the PK properties of infliximab in pediatric and adult patients with moderately to severely active CD, first separately and then combined, and identified important covariates of the PK parameters in these populations. Simulations were conducted to explore quantitative extrapolation of the effects of covariates identified in the adult population to the pediatric population, in whom data for such covariates were either inadequate or unavailable.
Section snippets
Materials and Methods
This analysis used data from patients with moderately to severely active CD in the pediatric and adult populations (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease]13 and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]).9
Patient Populations
A total of 112 pediatric patients were enrolled in REACH (66 boys, 46 girls; median age, 13 years; median weight, 42 kg; median PCDAI, 41.2) (Table I). Thirty-five percent of patients were receiving corticosteroids at baseline. One hundred three patients were randomly assigned to treatment.
ACCENT I enrolled 580 patients (241 men; 339 women; median age, 35.5 years; median weight, 68.5 kg), with 573 assigned to treatment.
The combined pediatric and adult populations included 692 patients, with
Discussion
The availability of 2 Phase III clinical studies in patients with moderately to severely active CD—one each in children and adults—allowed for the comparison of infliximab population PK properties between these populations. Typical population PK analysis employs total dose and examines the allometric relationship between the PK parameters of a drug (eg, CL, Vd) and weight changes.39 This approach may be useful for establishing or investigating the variability of PK parameters expected over the
Conclusions
Based on the findings from the present analysis, the disposition of infliximab in both pediatric and adult patients with CD appeared to be affected strongly by baseline SAC and ATI status and weakly by concurrent immunomodulator administration. The intrinsic Vd of infliximab per kg body weight decreased as the total weight (not age) increased in pediatric and adult patients; thus, exposure appeared similar between similarly weighted pediatric and adult patients with CD who were administered the
Acknowledgments
This research was supported by a research grant from Centocor Research and Development, Inc. The REACH and ACCENT I clinical trials were sponsored by Centocor Research and Development, Inc.
The authors thank the patients, investigators and study personnel who made the REACH and the ACCENT I studies possible. They also thank Mr. James P. Barrett, Medical Affairs Publication Group, Medical Affairs, Centocor Ortho Biotech, Inc., for editorial support.
The authors were employees of Centocor Research
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2023, Gastroenterology Clinics of North AmericaImpact of proactive of infliximab monitoring using the Bayesian approach in the maintenance phase in patients with inflammatory bowel disease
2023, Gastroenterologia y HepatologiaCitation Excerpt :The multicentre, prospective PANTs study showed that the main factor independently associated with primary non-response was low infliximab concentration at weeks 14 and 54.9 Many studies have shown high inter-individual variability in serum infliximab concentrations.10,11 Factors that can lead to low infliximab exposure include high inflammatory burden with high CRP, faecal calprotectin, low albumin and haemoglobin.