P531 A model-based tool for guiding infliximab induction dosing to maximise long-term deep remission in children with inflammatory bowel diseases
Kantasiripitak, W.(1);WIcha, S.G.(2);Thomas, D.(1);Hoffman , I.(3);Ferrante , M.(4,5);Vermeire , S.(4,5);van Hoeve , K.(3);Dreesen, E.(1,6)*;
(1)University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium;(2)University of Hamburg, Department of Clinical Pharmacy, Hamburg, Germany;(3)University Hospitals Leuven, Department of Paediatric Gastroenterology- Hepatology- and Nutrition, Leuven, Belgium;(4)University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium;(5)University of Leuven, Department of Chronic Diseases and Metabolism, Leuven, Belgium;(6)University of California, Department of Bioengineering and Therapeutic Sciences, Leuven, Belgium;
Background
Adequate infliximab (IFX) concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with Crohn’s disease (CD) and ulcerative colitis (UC).1 Under standard IFX induction dosing, children often have low IFX trough concentrations.2 Model-informed precision dosing (MIPD) is advocated as a promising IFX dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric IFX induction treatment.
Methods
Data from 31 children (4-18 years, 15-76 kg, 20:11 CD:UC) receiving standard IFX induction dosing (5 mg/kg at week [w]0, w2, and w6) were repurposed.1 Eight paediatric population pharmacokinetic models were evaluated (six 2-compartment models and two 1-compartment models). Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and to develop a multi-model prediction algorithm for implementation into an MIPD software tool.3 A role for IFX clearance monitoring was evaluated.
Results
A total of 251 IFX concentrations were available (6-10 samples per patient). One patient had undetectable IFX concentrations at w6 and w12 but had no measurable antibodies to IFX (ATI). At six months after start of the IFX treatment, 58% (18/31) of patients achieved deep remission.
The measured IFX concentration at w12 was the best predictor and classifier for deep remission. A 7.5 mg/L IFX concentration target at w12 was associated with a 64% probability of deep remission at six months (Figure 1). With standard dosing, less than 80% of simulated children <40 kg attained this target (Figure 2). Immunomodulator combo-therapy only subtly improved probability of target attainment. Presence of ATI lowered the target attainment considerably.
The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 IFX concentration. The multi-model algorithm outperformed single models when optimising the w6 dose based on combined w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. The predictive performance of the MIPD multi-model algorithm was robust to misspecification of ATI status.
IFX clearances at w6 and w12 were predictive for deep remission (P=0.02) (Figure 3).
An IFX module was added to the TDMx software tool to facilitate MIPD and clearance monitoring (https://tdmx.shinyapps.io/Infliximab_paediatric/).
Conclusion
A freely available, interactive, multi-model MIPD software tool is provided to facilitate IFX induction dosing and improve deep remission rates in children with CD and UC.
1van Hoeve et al. J Pediatr 2022.
2van Rheenen et al. J Crohns Colitis 2020.
3Kantasiripitak et al. CPT:PSP 2022.