Pharmacokinetics and exposure-response relationships of ustekinumab in patients with ulcerative colitis: Results from the UNIFI induction and maintenance studies

INTRODUCTION:

Serum concentrations of monoclonal antibody-based biologics have been shown to correlate with their efficacy. PK, exposure-response (ER), and immunogenicity of ustekinumab (UST) were evaluated in UNIFI induction and maintenance studies in UC. Induction results were presented previously.

METHODS:

PK, immunogenicity, efficacy & safety data were obtained from induction and maintenance Phase 3, double-blind, PBO-controlled trials in adults with moderate-severe UC. Pts (n = 961) in the induction study received a single IV infusion at Wk0 of PBO, UST 130 mg, or UST ∼6 mg/kg UST. Responders to a single IV infusion of UST (n = 523) were randomly assigned to receive SC PBO, UST 90 mg q12w, or UST 90 mg q8w. Blood samples were collected to measure serum UST concentration and antibodies to ustekinumab. Relationships between serum UST concentrations & efficacy measures, and safety outcomes were evaluated.

RESULTS:

Serum UST concentrations over time were dose proportional, unaffected by concomitant immunosuppressants, & similar between pts who were biologic failures & non-failures. Median peak serum UST concentrations in the induction study were 43.2 μg/mL & 127.0 μg/mL for the 130 mg & ∼6 mg/kg dose groups, respectively. At induction Wk8, median UST concentrations were 2.51 mg/ mL & 8.59 μg/mL, respectively. Steady-state was reached by the start of the second SC maintenance dose. Median steady-state trough serum UST concentrations over time in the UST q8w group (2.69 to 3.09 μg/mL) were 3-fold higher than in the q12w group (0.92 to 1.19 μg/mL). Serum UST concentrations were positively associated with response & remission rates (Table 1), and there was an inverse association between serum UST concentrations and CRP and fecal calprotectin levels. No relationship was observed between serum UST concentrations & the incidence of infections, serious infections or SAEs during induction or maintenance. 3.4% of pts receiving UST maintenance had antibodies to UST through 1 year using a drug-tolerant assay vs. 9.1% with PBO; no impact of antibodies on efficacy was observed.

CONCLUSION:

Serum UST concentrations were approx. dose-proportional. A positive ER of serum UST with clinical efficacy measures and an inverse relationship with inflammatory markers was observed during UST IV induction & SC maintenance. Adverse events including infections did not increase with increased serum UST concentrations. These findings are consistent with those in UST for Crohn's disease.