Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease

Abstract

Objectives: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. Methods: A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. Results: Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. Conclusions: Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.

Pediatric Dose Selection for Therapeutic Proteins

“…However, half of the patients required an increased dose or a shortened dosing interval to maintain a clinical response 29 . While the dose adjustments in the REACH trial were based on clinical evaluation and response, a target trough concentration of 3 to 5 μg/mL was soon identified for therapeutic drug monitoring in practice 30–32 . Revisiting the original analyses by Fasanmade et al revealed that 60% of children would achieve subtherapeutic trough concentrations with the labeled dose 33 .…”

“…The European Society for Paediatric Gastroenterology Hepatology and Nutrition subsequently revised their recommendations and advocates for up‐front intensification of the induction regimen for children <10 years of age 31 . Results of a systematic review further suggest that dose increases are necessary for all pediatric patients with inflammatory bowel disease with low serum albumin or with no concurrent immunomodulator therapy 32 . In retrospect, it can be concluded that the adult weight‐based dosing was not appropriate for the pediatric label 32 …”

“…Results of a systematic review further suggest that dose increases are necessary for all pediatric patients with inflammatory bowel disease with low serum albumin or with no concurrent immunomodulator therapy 32 . In retrospect, it can be concluded that the adult weight‐based dosing was not appropriate for the pediatric label 32 …”

Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study

“…Furthermore, only patients with IBD had detectable ADAs in our cohort, begging the question whether the real-world dosing practices observed in our IBD cohort (median [IQR] of 7.7 [6.2,9.4] mg/kg every 6 [4,8] weeks) are adequate to prevent loss of treatment response to IFX. Two other recent analyses have similarly questioned the adequacy of standard 5 mg/kg IFX dosing every 8 weeks for pediatric IBD, advocating for treat-to-target approaches for IFX [25,26]. No patients with uveitis or JIA had ADAs or trough levels < 5 μg/mL, however, unlike IBD, there are no established IFX therapeutic trough targets currently utilized for JIA or uveitis.…”

Therapy outcome related to adalimumab trough levels in pediatric patients with inflammatory bowel disease

“…For adalimumab, the approved induction regimen in PIBD ranges from 40 mg at week 0 and 20 mg at week 2 to 160 mg at week 0 and 80 mg at week 2 based on the weight of the patient, and disease severity assessed by a physician. Maintenance therapy with adalimumab is administered biweekly but may be enhanced to weekly therapy and/or by doubling the maintenance dose [8,9]. Infliximab and its biosimilars are licensed for use in children who are at least six years of age and have moderate to severe Crohn's disease or ulcerative colitis, and adalimumab only recently for such patients with ulcerative colitis in addition to Crohn's disease.…”