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

• Main Authors: Wannee Kantasiripitak (Author), An Outtier (Author), Sebastian G. Wicha (Author), Alexander Kensert (Author), Zhigang Wang (Author), João Sabino (Author), Séverine Vermeire (Author), Debby Thomas (Author), Marc Ferrante (Author), Erwin Dreesen (Author)
• Format: Book
• Published: Wiley, 2022-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2163-8306; 10.1002/psp4.12813
• Keywords: Therapeutics. Pharmacology; RM1-950
• Source: CPT: Pharmacometrics & Systems Pharmacology, Vol 11, Iss 8, Pp 1045-1059 (2022)

Abstract Infliximab dosage de‐escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single‐model approach for model‐informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multi‐model approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de‐escalation. Data of 54 patients with Crohn's disease and ulcerative colitis who underwent infliximab dosage de‐escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%-63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single‐model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single‐ and multi‐model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five‐fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de‐escalation in the forthcoming prospective MODIFI study (NCT04982172).