Editorial: subcutaneous CT‐P13 in Crohn’s disease and ulcerative colitis–small change, big consequences. Authors' reply

We thank Prof Carbonnel and Dr Meyer for their insightful editorial1 on our population pharmacokinetic model of subcutaneous infliximab CT-P13 in inflammatory bowel disease.2 We agree that several important questions remain to be answered by ongoing Phase 3 studies and wider adoption of subcutaneous CT-P13 in real-world cohorts.

The most clinically relevant finding in our study was that trough concentrations obtained with intravenous dosing cannot be directly compared to those with subcutaneous dosing. For the sake of simplicity and convenience, trough concentrations, as opposed to the area under the curve, have been almost universally used in exposure-response analyses of biologic drugs in inflammatory bowel disease. Despite the accumulating evidence for a strong correlation between the area under the curve and efficacy in inflammatory bowel disease,3 it is uncertain whether calculating cumulative exposure with a pharmacokinetic model to guide dosing in clinical practice offers an advantage over merely shifting the range of concentrations associated with favourable outcomes based on clinical studies with the subcutaneous formulation.4

Our model was developed in a population of biologic-naïve patients with those in the intravenous dosing arm receiving 5 mg/kg every 8 weeks.5 Caution may be required when switching patients with a shorter dosing interval or higher dosing of infliximab to subcutaneous CT-P13. Notably, in patients with perianal fistulising disease, higher concentrations of infliximab (>10 mg/L with intravenous dosing), which are seldom attained with dosing per label, were associated with fistula healing.6 Switching from intravenous to subcutaneous dosing in these patients while relying on the numerically higher trough concentrations with subcutaneous could result in the re-opening of perianal fistulas.

Future research in biologic-experienced patients with inflammatory bowel disease is expected to further elucidate the pharmacokinetics of subcutaneous CT-P13, as there is evidence for increased clearance of biologic drugs in these patients.7, 8 These patients may also have experienced loss of response due to the development of anti-drug antibodies to their previous biologic drug and the hypothesis that intravenous induction followed by subcutaneous maintenance dosing offers an advantage in terms of immunogenicity warrants testing in this population.

As Carbonnel and Meyer have highlighted, immunogenicity is an important concern with subcutaneously administered infliximab. In bionaïve patients, the development of any anti-drug antibodies measured with a drug-tolerant assay were similar regardless of administration route (69.7% subcutaneous and 63.5% intravenous), although there were fewer neutralizing antibodies with subcutaneous dosing (18.2% vs 36.9%).5 Overall safety was comparable between arms, which was also demonstrated for patients with rheumatoid arthritis.9, 10 Furthermore, the incidence of study drug administration-related reactions (infusion-related reactions, systemic injection reactions, delayed hypersensitivity reactions) during the treatment period was low: 7.6% in the subcutaneous and 4.6% in the intravenous arm.5

We agree with Carbonnel and Meyer that the efficacy, safety and practicalities of transitioning from intravenous to subcutaneous administration remain to be tested in larger and more varied patient populations.

The authors' declarations of personal and financial interests are unchanged from those in the original article.2

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