An Observational Study of Methotrexate Pharmacokinetics and Pharmacodynamics in Paediatric and Adolescent Patients with Crohn’s Disease

The primary objective of this study is the determination of methotrexate polyglutamate (MTX-PG) concentrations and the identification of accumulation patterns over time in erythrocytes. Additionally, the study evaluates the association between MTX-PG concentration and methotrexate discontinuation resulting from a lack of efficacy or toxicity.

Secondary objectives include:

• Identification of clinical, genetic, and metabolic determinants influencing MTX-PG accumulation patterns in erythrocytes.
• Comparison of MTX-PG concentrations between erythrocytes and peripheral blood mononuclear cells.
• Evaluation of the association between the faecal microbiome, metabolome, and MTX-PG accumulation.
• Assessment of the association between MTX-PG concentration and discontinuation due to lack of efficacy, including the determination of a responder cut-off.
• Investigation of the association between MTX-PG concentration and discontinuation due to hematological, hepatic, or gastrointestinal toxicity.
• Development of predictive models for efficacy and toxicity prior to the initiation of treatment.
• Analysis of the association between MTX-PG accumulation patterns, infliximab dosage, infliximab levels, and anti-drug antibodies in patients receiving combination therapy.

The sponsor did not provide information regarding the total number of participants. The study population consists of patients diagnosed with Crohn’s disease, confirmed through endoscopic, radiological, and histologic findings. The cohort includes both male and female individuals within an age range of 4 to 28 years. Participants are required to initiate methotrexate treatment as either monotherapy or in combination therapy with infliximab. The study objectives include:

• Determination of methotrexate polyglutamate concentrations and identification of accumulation patterns over time in red blood cells.
• Association of methotrexate polyglutamate concentration with methotrexate discontinuation due to a lack of efficacy or toxicity.

This phase IV observational study aims to investigate the pharmacokinetics and pharmacodynamics of methotrexate in patients with Crohn’s disease. The research focuses on determining methotrexate polyglutamate (MTX-PG) concentrations in red blood cells (RBCs) and identifying accumulation patterns over time. Additionally, the study evaluates the association between MTX-PG concentrations and drug survival, which is defined as the cumulative incidence of methotrexate monotherapy discontinuation during the first year due to treatment failure or toxicity. Participants aged 4 to 28 years who are starting methotrexate as monotherapy or in combination with infliximab will be included. The study protocol involves several scheduled visits to collect data at baseline, 1, 3, 6, and 12 months. During these visits, clinical, genetic, and metabolic parameters will be assessed, including fecal calprotectin, C-reactive protein (CRP), and disease activity scores. The primary investigation of RBC MTX-PG levels will occur at the 1, 3, and 6-month intervals. The observational period for each participant extends through the first year of treatment, with the overall study recruitment and observation scheduled to conclude by February 2030. Early termination of treatment may occur if discontinuation is required due to lack of efficacy or adverse effects.

The experimental treatment involves the administration of methotrexate. One formulation is provided as a solution for injection in a prefilled pen, administered via a subcutaneous route at a dose of 3.57 mg. Another formulation is provided as tablets for oral administration at a dose of 3.57 mg.

Efficacy assessment in this study of Crohn’s disease involves several pharmacological and clinical parameters. The primary pharmacokinetic endpoint is the measurement of RBC MTX-PG levels at 1, 3, and 6 months. The primary pharmacodynamic endpoint is drug survival, which is defined as the cumulative incidence of methotrexate monotherapy discontinuation during the first year due to treatment failure or toxicity. Treatment failure is characterized by the requirement for surgery, thiopurine therapy, JAK inhibitors, biologicals, or systemic corticosteroids due to inflammation from a disease flare.

Secondary efficacy evaluations include:

• PBMC MTX-PG levels at 1, 3, and 6 months.
• Disease activity scores, faecal calprotectin, C-reactive protein, and the SIBDQ measured at baseline, 1, 3, 6, and 12 months.
• Drug survival specifically attributed to treatment failure.
• Evaluation of infliximab levels and anti-drug antibodies to infliximab.