Model-Informed Precision Dosing during Infliximab Induction Therapy Reduces Variability in Exposure and Endoscopic...

Model-informed precision dosing (MIPD) may be a solution to therapeutic failure of infliximab for patients with ulcerative colitis (UC), as underexposure could be avoided, and the probability of endoscopic improvement (pEI; Mayo endoscopic subscore ≤ 1) could be optimized. To investigate in silico whether this claim has merit, four induction dosing regimens were simulated: 5 mg/kg (label dosing), 10 mg/kg, covariate-based MIPD (fat-free mass, corticosteroid use, and presence of extensive colitis at baseline), and concentration-based MIPD (based on the trough concentration at day 14). Covariate- and concentration-based MIPD were chosen to target the same median area under the infliximab concentration-time curve up to endoscopy at day 84 (AUC_d84), as was predicted from 10 mg/kg dosing. Dosing at 5 mg/kg resulted in a mean ± standard deviation pEI of 55.7 ± 9.0%. Increasing the dose to 10 mg/kg was predicted to improve pEI to 65.1 ± 6.1%. Covariate-based MIPD reduced variability in exposure and pEI (65.1 ± 5.5%). Concentration-based MIPD decreased variability further (66.0 ± 3.9%) but did so at an increased average dose of 2293 mg per patient, as compared to 2168 mg for 10 mg/kg dosing. Mean pEI remained unchanged between 10 mg/kg dosing and MIPD, since the same median AUC_d84 was targeted. In conclusion, quantitative simulations predict MIPD will reduce variability in exposure and pEI between patients with UC during infliximab induction therapy.