Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease: results from a randomized, multicenter, phase-3 study.
BACKGROUND
Adalimumab, a fully human monoclonal antibody (IgG1κ) to tumor necrosis factor, has shown benefit in the treatment of inflammatory bowel disease. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and the serum concentration-efficacy relationship of adalimumab in pediatric patients with moderate-to-severe Crohn's disease.


METHODS
The safety, efficacy, and PK of adalimumab was evaluated in a phase-3, randomized, double-blind, 52-week study (IMAgINE-1, N = 192), which had a 4-week open-label induction phase (dose was determined by patient weight) followed by a 48-week double-blind maintenance phase (standard and low-dose arms, drug given every other week). Trough serum adalimumab (baseline, weeks 2, 4, 16, 26, and 52) and anti-adalimumab antibody measurements (baseline, weeks 16, 26, and 52) were collected. Disease activity was assessed using the Pediatric Crohn's Disease Activity Index.


RESULTS
At week 52, adalimumab trough concentrations (mean ± SD) were higher for patients in the standard-dose (9.48 ± 5.61 μg/mL) compared with the low-dose (3.51 ± 2.21 μg/mL) arm. In patients whose doses were increased from every other week to weekly, higher trough concentrations were observed after dose escalation. Higher body weight, baseline C-reactive protein, and lower baseline albumin levels were associated with greater clearance of adalimumab. An exposure (serum concentration)-efficacy relationship was observed, in which higher concentrations of adalimumab were associated with greater rates of remission.


CONCLUSIONS
This study is the first to describe the PK of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. A positive association between serum adalimumab concentration and remission/response was identified.
*Global Pharmaceutical Research and Development Division, AbbVie Inc., North Chicago, Illinois; †AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany; ‡Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut; §Division of Gastroenterology and Nutrition, Goryeb Children's Hospital-Atlantic Health, Morristown, New Jersey; and ‖Service de gastroentérologie-hépatologie-nutrition pédiatriques, Hôpital Necker-Enfants Malades, Paris, France.
Shringi
S
Sharma
Doerthe
D
Eckert
Jeffrey S
JS
Hyams
Sven
S
Mensing
Roopal B
RB
Thakkar
Anne M
AM
Robinson
Joel R
JR
Rosh
Frank M
FM
Ruemmele
Walid M
WM
Awni
D000068879:Adalimumab / Q000008:administration & dosage* / Q000097:blood; D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001835:Body Weight; D002097:C-Reactive Protein / Q000032:analysis; D002648:Child; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D012709:Serum Albumin / Q000032:analysis
D000893:Anti-Inflammatory Agents; D012709:Serum Albumin; D002097:C-Reactive Protein; D000068879:Adalimumab