Erwin Dreesen1, Sophie Berends2, David Laharie3, Geert D'Haens4, Séverine Vermeire5, Ann Gils1, Ron Mathôt2. 1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 2. Hospital Pharmacy, Amsterdam UMC, Amsterdam, Netherlands. 3. Department of Hepato-gastroenterology and Digestive Oncology, Haut-Lévêque Hospital, Bordeaux UMC, Bordeaux, France. 4. Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, Netherlands. 5. Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
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 [fCal] 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 fCal; and a first-order Markov popPD model linking fCal to transitions between states of ER, no ER and dropout. RESULTS: Infliximab clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of anti-drug antibodies. Baseline fCal increased with increasing C-reactive protein and decreasing platelet count. Lower fCal 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 fCal concentration (while accounting for PK and PD variability) may improve effectiveness of infliximab therapy.
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 [fCal] 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 fCal; and a first-order Markov popPD model linking fCal to transitions between states of ER, no ER and dropout. RESULTS:Infliximab clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of anti-drug antibodies. Baseline fCal increased with increasing C-reactive protein and decreasing platelet count. Lower fCal 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 fCal concentration (while accounting for PK and PD variability) may improve effectiveness of infliximab therapy.
Authors: Wannee Kantasiripitak; An Outtier; Sebastian G Wicha; Alexander Kensert; Zhigang Wang; João Sabino; Séverine Vermeire; Debby Thomas; Marc Ferrante; Erwin Dreesen Journal: CPT Pharmacometrics Syst Pharmacol Date: 2022-06-15
Authors: Jurij Hanzel; Erwin Dreesen; Séverine Vermeire; Mark Löwenberg; Frank Hoentjen; Peter Bossuyt; Esmé Clasquin; Filip J Baert; Geert R D'Haens; Ron Mathôt Journal: Inflamm Bowel Dis Date: 2022-05-04 Impact factor: 7.290