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.

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Zhang W, Scalori A, Fuh F, McBride J, She G, Kierkus J, Korczowksi B, Li R, Abouhossein M, Kadva A, Park KT, Tang MT

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.

Inflamm Bowel Dis. 2021 Nov 29. pii: 6446094. doi: 10.1093/ibd/izab275.

PubMed ID
34849918 [ View in PubMed
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Abstract

BACKGROUND: Etrolizumab, a humanized anti-beta7 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 (Cmax) was 9.8 (4.86) microg/mL and 18.1 (6.25) microg/mL; and mean (SD) area under the curve within a dosing interval (AUCtau) was 167 (86.9) and 521 (306) mug.day/mL after the last dose. The Cmax 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 beta7high gut-homing T and B cell subsets declined below 10% of baseline, confirming beta7 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 Cmax and a slightly greater than dose-proportional increase in AUCtau. Both regimens achieved complete/near-complete beta7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.

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