Modelling of the relationship between infliximab exposure, faecal calprotectin and endoscopic remission in patients with Crohn's disease. Issue 1 (3rd June 2020)

• Record Type: Journal Article
• Authors: Dreesen, Erwin; Berends, Sophie; Laharie, David; D'Haens, Geert; Vermeire, Séverine; Gils, Ann; Mathôt, Ron
• Is Part Of: British journal of clinical pharmacology. Volume 87:Issue 1(2021)
• Page Start: 106
• Page End: 118
• Publication Date: 2020-06-03
• Subjects: Crohn's disease -- infliximab -- pharmacometrics -- population pharmacokinetics–pharmacodynamics -- therapeutic drug monitoring; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14364
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring of infliximab in patients with Crohn's disease (CD) remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the infliximab dose–exposure–biomarker–response (faecal calprotectin [ f Cal] and endoscopic remission [ER]) relationship. Methods: Data were obtained from 116 patients with CD in a phase 4 dose‐escalation study. Three sequential models were developed: a 2‐compartment popPK model linking infliximab dose to exposure; an indirect response popPK/PD model describing the inhibitory effect of infliximab exposure on f Cal; and a first‐order Markov popPD model linking f Cal to transitions between states of ER, no ER and dropout. Results: Infliximab clearance increased with increasing f Cal, decreasing albumin, increasing CD activity index and presence of anti‐drug antibodies. Baseline f Cal increased with increasing C‐reactive protein and decreasing platelet count. Lower f Cal increased the probability of attaining ER and decreased the probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with time. Large interpatient PK and PD variability resulted in a flat dose–response curve. Predicted fraction of patients achieving ER was 45% [30–61] (median [interquartile range], n = 50 000) when on 5 mg/kg infliximab (~46% observed in data). Simulations with 10 mg/kg induction doses predicted an increase to 48% [32–63]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients. Conclusion: Model‐informed infliximab dose optimisation towards a predefined f Cal concentration (while accounting for PK and PD variability) may improve effectiveness of infliximab therapy.