Population Pharmacokinetics and Exposure‐Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis

Abstract

Population pharmacokinetics (PK) and exposure‐response (E‐R) analyses were conducted to compare the PK and E‐R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6‐17 years) in the PURSUIT‐PEDS‐PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2‐17 years) in the GO‐KIDS study, were included in the population PK analysis. E‐R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score–based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1‐compartment model with first‐order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model‐estimated terminal half‐life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT‐PEDS‐PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E‐R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E‐R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.

Golimumab in adolescents with Crohn’s disease refractory to previous tumor necrosis factor antibody

“…Following GLM, only 2/7 patients still exhibit moderate/severe disease activity. Similar to Merras-Salmio et al, all patients responded to the first injection of GLM [28] or to Hyams et al, were at week 6 clinical response was achieved in 60% and clinical remission in 42,6% [25][26][27]. It can be speculated that the superior affinity of GLM to TNF-α and TNF-α induced cytotoxicity might have influenced this positive outcome.…”

“…However, serum GLM concentrations were generally lower in the < 45 kg than ≥ 45 kg weight subgroup. Three subjects were even positive for antibodies to GLM [25][26][27]. Although the majority of our patients were ≥ 45 kg weight subgroup, in our cohort GLM doses needed to be increased in four patients after 10 weeks.…”

“…This was in line with Merras-Salmio et al, where the response also did not last until the third dose at four weeks and the inflammatory markers started to increase, all their patients needed therapy escalation at two to six months [28]. However similar to Merras-Salmi et al [28], doses used in our retrospective study were heterogeneous, both cohorts included CD patients and were not naïve to anti-TNF therapy, and hence it is difficult to draw any firm conclusions about optimal dosing and compare the results with the latest PK studies in paediatric UC patients [25][26][27].…”

“…Since we have no histology details from the responders is it difficult to draw a conclusion about the effect of GLM on luminal disease. However in the recent study in UC children, mucosal healing as evaluated by sigmoidoscopy/colonoscopy at week 6 (Mayo endoscopy subscore ≤ 1) was achieved in 54.3% of subjects and 22.9% achieved complete healing (Mayo endoscopy subscore 0) [25][26][27].…”

“…GLM is currently not licensed for the use in paediatric inflammatory bowel disease (IBD) patients, however a recent international multicentre study in 35 children aged 6-17 years with UC naïve to any TNF-a antibody showed at week 6 54% mucosal healing with no clinically important safety concerns [11,[25][26][27].…”