Zhigang Wang1; Bram Verstockt2,3; João Sabino2,3; Séverine Vermeire2,3; Marc Ferrante2,3; Paul Declerck1; Erwin Dreesen1,4
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 4 Department of Pharmacy, Uppsala University, Uppsala, Sweden
Objectives: Ustekinumab is a fully human monoclonal antibody that is approved for the treatment of patients with moderate-to-severe Crohn’s disease (CD). In the UNITI endoscopy sub-study, only 17.4% of patients with CD on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44 [1]. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modeling and simulation analysis.
Methods: Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-drug refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (~6mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg) [2]. Ustekinumab serum concentrations were measured during induction (w4) and at trough (w8, w16, w24) using an enzyme-linked immunosorbent assay (ELISA) with lower limit of quantification (LLOQ) of 0.25 µg/mL. Fecal calprotectin (fCal) was measured at baseline, and at w4, w8, w16, w24 using an ELISA with LLOQ 30 µg/g and upper limit of quantification (ULOQ) 1,800 µg/g. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24.
A total of 3,000 virtual patients were created and equally randomized into either the q4w or the q8w dosing arm (1:1 randomization). Individual covariates were sampled following a truncated normal distribution with boundaries equal to the range of the covariate in our data set.
Modeling and simulation were performed using NONMEM 7.4. The M3 method was used to handle concentrations below or above the LOQ.
Results: Three sequential models were developed: a 2-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24. Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. Volumes of distribution (**1), and clearances (**0.75) were allometrically scaled. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 34.3% with fCal at w8 decreasing from 1,800 µg/g to 30 µg/g. The probability of endoscopic remission at w24 increased from 2.1% to 17.5% with fCal at w8 decreasing from 1,800 µg/g to 30 µg/g. The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Study sample sizes of 1,396 and 774 patients per dosing arm would be required for identifying statistically significant differences in the rates of endoscopic response (NNT=18) and endoscopic remission (NNT=44), respectively, between both study arms (1:1 randomization, α=5%, power=80%).
Table 1. Simulation of q4w and q8w ustekinumab maintenance dosing
|
Simulated results at steady state |
q8w 90mg |
Q8w 180mg |
q4w 90mg |
|
Median trough serum concentration of ustekinumab |
1.3 µg/mL |
2.7 µg/mL |
5.3 µg/mL |
|
Median trough concentration of fecal calprotectin |
796 µg/g |
548 µg/g |
424 µg/g |
|
Endoscopic remission rate |
4.2% |
5.6% |
6.7% |
|
Endoscopic response rate |
16.7% |
20% |
22.2% |
Abbreviations: q4w, maintenance dosing every 4 weeks; q8w, maintenance dosing every 8 weeks.
Conclusion: The developed model can guide clinical trial design and support model-informed dose optimization to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in lower fCal concentrations, the proportion of patients achieving endoscopic remission was still limited.
References:
[1] Rutgeerts P, Gasink C, Chan D, et al. Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn’s Disease. Gastroenterology. 2018;155(4):1045-1058.
[2] Verstockt B, Dreesen E, Noman M, et al. Ustekinumab Exposure-outcome Analysis in Crohn’s Disease only in Part Explains Limited Endoscopic Remission Rates. J Crohn’s Colitis. 2019;13(7):864-872.
Reference: PAGE 29 (2021) Abstr 9839 [www.page-meeting.org/?abstract=9839]
Poster: Drug/Disease Modelling - Other Topics