Zhigang Wang (1), Wannee Kantasiripitak (1), An Outtier (2,3), Debby Thomas (1), João Sabino (2,3), Séverine Vermeire (2,3), Marc Ferrante (2,3), Erwin Dreesen (1)
(1) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (2) Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (3) Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
Objectives:
Extending the dosing interval between infliximab infusions has been attempted in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who sustained treatment response following an earlier interval shortening. We aimed to identify predictors of sustained remission and an optimal trough concentration (TC) target for sustained remission after infliximab interval extension.
Methods:
Data from 30 adult patients (17 CD, 13 UC) who underwent infliximab interval extension following earlier interval shortening, were collected from a single-centre database search. All patients were in steroid-free clinical remission (two-item patient-reported outcome [PRO2] ≤1 [UC] and ≤8 [CD]) and biological remission (C-reactive protein [CRP] <5 mg/L or faecal calprotectin [FC] <250 mg/kg) at the start of interval extension.
We developed a time-to-event (TTE) model to describe the time to relapse – defined as loss of steroid-free clinical and biological remission – during one year after infliximab interval extension (NONMEM7.5). Various hazard functions were explored, and disease type and time-varying infliximab TCs and clearance were investigated as predictors of the relapse hazard risk. Infliximab clearance was predicted a posteriori using weighted averaging of the estimates of 18 population pharmacokinetics models [1]. Model building was guided by objective function value comparisons and Kaplan-Meier visual predictive check plots. The TTE model was used to simulate (n=2000) model-informed infliximab interval extension aimed at infliximab TCs ranging from 5 to 15 mg/L.
Results:
Overall, 37% (n=11) of patients remained relapse-free until one year after infliximab interval extension (5 CD, 6 UC). The proportion of patients with a TC above 5 mg/L – the widely accepted target concentration [2] – was 66% (19/29; one missing) at baseline and 48% (12/25; five missing) at one year. The median TC at one year after infliximab interval extension was 4.7 [range 1.6–10.8] mg/L in patients with CD and 4.9 [range 2.6–6.8] mg/L in patients with UC. TCs were not significantly different between relapsed and relapse-free patients during one year.
A time-constant (exponential) hazard model best described the relapse data of patients with CD. A Gompertz hazard model best described the data of patients with UC, with the relapse hazard risk increasing over time. Patients with CD had an overall 12-fold higher baseline hazard of relapse than patients with UC. For patients with UC, the infliximab TC was inversely related to the relapse hazard risk and was included in the model using an inhibitory Emax function. The functions of the two final hazard models are:
CD: 0.0035
UC: 0.00029 * exp[0.0198*time* (1-InfliximabTC/(InfliximabTC+3.14))]
The proportion of UC patients with sustained remission one year after interval extension was predicted to increase from 57% [95% prediction interval 54–60%] to 81% [95% PI 79–84%] with the targeted TC increasing from 5.0 to 15.0 mg/L (Table 1).
Conclusions:
An exposure-response relationship was observed for infliximab in patients with UC but not CD. In patients with UC, the hazard risk increased with time, but this risk was lower when the infliximab TC increased, which supports a role for model-informed infliximab interval extension in patients with UC.
Table 1. Simulated rates of sustained remission until one year after infliximab interval extension in 1000 patients with ulcerative colitis
|
TC target |
Sustained remission rate in UC Mean (95% PI) |
|
Dataset (4.9 mg/L) |
46% [19–75%] |
|
5.0 mg/L |
57% [54–60%] |
|
6.0 mg/L |
63% [61–66%] |
|
7.0 mg/L |
68% [65–71%] |
|
8.0 mg/L |
71% [68–74%] |
|
9.0 mg/L |
74% [71–77%] |
|
10.0 mg/L |
76% [73–79%] |
|
11.0 mg/L |
77% [75–80%] |
|
12.0 mg/L |
79% [76–81%] |
|
13.0 mg/L |
80% [77–82%] |
|
14.0 mg/L |
81% [78–83%] |
|
15.0 mg/L |
81% [79–84%] |
Abbreviations: PI, prediction interval; TC, infliximab trough concentration; UC, ulcerative colitis.
References:
[1] Kantasiripitak W et al. CPT PSP (2022) 11(8),1045-1059.
[2] Feuerstein JD et al. Gastroenterology (2017) 153(3),827-834.
Reference: PAGE 32 (2024) Abstr 11236 [www.page-meeting.org/?abstract=11236]
Poster: Drug/Disease Modelling - Other Topics