Population Pharmacokinetics and Exposure-Response Modeling Analyses of Ustekinumab in Adults With Moderately to Severely Active Ulcerative Colitis.

To characterize the pharmacokinetics (PK) and exposure-response (E-R) relationship of ustekinumab, an anti-interleukin-12/interleukin-23 (IL-12/IL-23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E-R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration-time data of ustekinumab were adequately described by a 2-compartment linear PK model with first-order absorption and first-order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E-R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E-R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90-mg subcutaneous every-8-week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90-mg subcutaneous every-12-week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E-R in a modeling framework to support ustekinumab dose recommendations in patients with UC.