Pharmacokinetics, Pharmacodynamics, and Safety of Etrolizumab in Children With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease: Results from a Phase 1 Randomized Trial

Background Etrolizumab, a humanized anti-beta 7 antibody, has not been studied in children. Here, we evaluate the pharmacokinetics, pharmacodynamics, and safety of etrolizumab in children with inflammatory bowel disease. Methods Patients age 4 to 17 years with moderately to severely active ulcerative colitis or Crohn's disease were randomized 1:1 to receive 1.5mg/kg of etrolizumab subcutaneously every 4 weeks (q4w) or 3.0mg/kg every 8 weeks (q8w) for 16 weeks in this open-label phase 1 trial. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results Of the 24 patients treated, 21 completed the study. In the groups of 1.5mg/kg q4w and 3.0mg/kg q8w, respectively, mean (SD) maximum concentration (C-max) was 9.8 (4.86) mu g/mL and 18.1 (6.25) mu g/mL; and mean (SD) area under the curve within a dosing interval (AUC(tau)) was 167 (86.9) and 521 (306) mu g center dot day/mL after the last dose. The C-max increased dose proportionally. The AUC over an 8-week period was slightly higher in the 3.0mg/kg q8w dose group. Median half-life was similar for both dosing regimens. Median numbers of free beta 7(high) gut-homing T and B cell subsets declined below 10% of baseline, confirming beta 7 target engagement and complete/near-complete receptor occupancy. Adverse events were consistent with the safety profile in adults. Approximately 60% of patients achieved a clinical response. Conclusions Etrolizumab showed a dose-proportional increase in C-max and a slightly greater than dose-proportional increase in AUC(tau). Both regimens achieved complete/near-complete beta 7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.

Automated summary

This study evaluated the pharmacokinetics, pharmacodynamics, and safety of Etrolizumab in children with inflammatory bowel disease. The results showed that Etrolizumab was well tolerated and demonstrated clinical activity in children.