Model-Informed Precision Dosing during Infliximab Induction Therapy Reduces Variability in Exposure and Endoscopic Improvement between Patients with Ulcerative Colitis

Abstract

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 (AUCd84), 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 AUCd84 was targeted. In conclusion, quantitative simulations predict MIPD will reduce variability in exposure and pEI between patients with UC during infliximab induction therapy.

Multi‐model averaging improves the performance of model‐guided infliximab dosing in patients with inflammatory bowel diseases

“…For infliximab, 18 PopPK models have been developed to describe the PK characteristics of adult patients with IBD. To date, the benefits of MIPD with a single infliximab model in patients with IBD have been evidenced both retrospectively 20 and prospectively 21 . However, alternative approaches that integrate multiple PopPK models have not been investigated for infliximab.…”

Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review

“…Moreover, out of the 26 evaluated publications, two used a virtual population [ 44 , 45 ], and two used previously published data [ 46 , 47 ], reducing the overall number of original studies to 22 (85% of the selected articles). The original study data extracted from the selected articles are presented in Table 1 .…”

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

“…MIPD of infliximab based solely on covariates (a priori prediction) has been shown to be biased and imprecise. 169,170 By incorporating 1 or more measured drug concentrations, the precision and accuracy of MIPD can be significantly improved. [169][170][171] This improvement is expected because covariates generally explain only a small part of the total interindividual variability (IIV, up to 6% for clearance), whereas Bayesian forecasting based on drug concentrations can identify the remaining, often high, "unexplained" IIV (median of 32.7%, interquartile range 28.0%-36.0% on clearance).…”

“…169,170 By incorporating 1 or more measured drug concentrations, the precision and accuracy of MIPD can be significantly improved. [169][170][171] This improvement is expected because covariates generally explain only a small part of the total interindividual variability (IIV, up to 6% for clearance), whereas Bayesian forecasting based on drug concentrations can identify the remaining, often high, "unexplained" IIV (median of 32.7%, interquartile range 28.0%-36.0% on clearance). 172,173 Second, there are significant efforts underway to enhance the methodological components of MIPD, focusing on methods for model selection 171,174,175 and the estimation of PK parameters.…”