Population pharmacokinetic-pharmacodynamic model-based exploration of alternative ustekinumab dosage regimens for patients with Crohn's disease

In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis.

Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (~6 mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes.

Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 μg/g to 694 μg/g (EC₅₀ ). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 μg/g to 214 μg/g (EC₅₀ ). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing.

The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.