Population Pharmacokinetics Analysis of Infliximab in up to 10-Year-Old Patients with Paediatric Inflammatory Bowel Disease: Label-Recommended Dose Fails to Achieve Therapeutic Target Concentration

Background and Objectives: Younger patients with paediatric inflammatory bowel disease (IBD) may require higher infliximab (IFX) doses to attain similar target trough levels compared with older paediatric and adult patients with IBD. This study aimed to investigate the population pharmacokinetics (popPK) of infliximab (IFX) in young paediatric patients with inflammatory bowel disease (IBD) (≤ 10 years old), optimize the IFX dosage in this special population and explore whether different IFX assays were comparable. Methods: IFX therapeutic drug monitoring (TDM) data from young paediatric patients with IBD (≤ 10 years old) were retrospectively collected from 14 European and Canadian centres (2015–2019). External validation of published popPK models was performed by calculating relative mean predictive errors (rMPE) and relative root mean square errors (rRMSE) to assess bias and imprecision. A refined popPK model was then developed using nonlinear mixed-effects modelling in NONMEM version 7.4. PopPK parameters in young paediatric patients with IBD (≤ 10 years old) were compared with those in published paediatric patients (> 10 to < 17 years) and adults. Results: In total, 2150 IFX concentrations from 104 young paediatric patients with IBD (≤ 10 years old) were measured by six different IFX assays. The median (min–max) age and body weight at start of IFX treatment of the population was 8.2 years old (1.2–10.0) and 25 kg (9.5–40.9), respectively. For the external validation, six published popPK models were evaluated. The best-performing model showed values for rMPE and rRMSE at 33.73% and 1189.59%, which rendered all models inadequate for our study population. Subsequently, a refined two-compartmental popPK model was developed. Typical clearance (CL) values (min–max, L/day/65 kg) were 0.615–0.943 for paediatric patients ≤ 10 years, 0.015–0.353 for published paediatric patients (> 10 to < 17 years) and 0.317–0.350 for published adults. Both albumin and C-reactive protein (CRP) could explain the inter-individual variability obtained in CL. Stratifying for IFX assays in the residual error model showed significant differences in relative prediction errors (rPE) between Immundiagnostik and an assay developed by Shomron Ben-Horin (named “in-house” assay) (P < 0.05) and between Caltag and in-house assays (P < 0.05). Post hoc individual CL differed between the Immundiagnostik and Sanquin assays (P = 0.033), while estimated area under the curve for weeks 6–14 (AUC_w6–14) remained similar (P > 0.05). With label-recommended dosing, IFX concentrations dropped below 5 mg/L for approximately 4 weeks during maintenance. Conclusions: Paediatric patients ≤ 10 years, demonstrated a higher IFX CL than paediatric patients > 10 to < 17 years and adults, with albumin and CRP explaining the variability of CL. The differences obtained across the IFX assays did not affect overall drug exposure. To maintain trough concentrations above 5 mg/L in paediatric patients ≤ 10 years, a dosing interval of 4 weeks is required.