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

Shringi Sharma, Doerthe Eckert, Jeffrey S. Hyams, Sven Mensing, Roopal B. Thakkar, Anne M. Robinson, Joel Rosh, Frank M. Ruemmele, Walid M. Awni

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Adalimumab, a fully human monoclonal antibody (IgG1) 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 g/mL) compared with the low-dose (3.51 ± 2.21 g/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.

Original languageEnglish (US)
Pages (from-to)783-792
Number of pages10
JournalInflammatory bowel diseases
Volume21
Issue number4
DOIs
StatePublished - Mar 6 2015

Fingerprint

Crohn Disease
Pharmacokinetics
Pediatrics
Serum
Adalimumab
Inflammatory Bowel Diseases
C-Reactive Protein
Anti-Idiotypic Antibodies
Albumins
Tumor Necrosis Factor-alpha
Immunoglobulin G
Monoclonal Antibodies
Body Weight
Maintenance
Safety
Weights and Measures

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Gastroenterology

Cite this

Sharma, Shringi ; Eckert, Doerthe ; Hyams, Jeffrey S. ; Mensing, Sven ; Thakkar, Roopal B. ; Robinson, Anne M. ; Rosh, Joel ; Ruemmele, Frank M. ; Awni, Walid M. / 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. In: Inflammatory bowel diseases. 2015 ; Vol. 21, No. 4. pp. 783-792.
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title = "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",
abstract = "Background: Adalimumab, a fully human monoclonal antibody (IgG1) 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 g/mL) compared with the low-dose (3.51 ± 2.21 g/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.",
author = "Shringi Sharma and Doerthe Eckert and Hyams, {Jeffrey S.} and Sven Mensing and Thakkar, {Roopal B.} and Robinson, {Anne M.} and Joel Rosh and Ruemmele, {Frank M.} and Awni, {Walid M.}",
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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. / Sharma, Shringi; Eckert, Doerthe; Hyams, Jeffrey S.; Mensing, Sven; Thakkar, Roopal B.; Robinson, Anne M.; Rosh, Joel; Ruemmele, Frank M.; Awni, Walid M.

In: Inflammatory bowel diseases, Vol. 21, No. 4, 06.03.2015, p. 783-792.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease

T2 - Results from a randomized, multicenter, phase-3 study

AU - Sharma, Shringi

AU - Eckert, Doerthe

AU - Hyams, Jeffrey S.

AU - Mensing, Sven

AU - Thakkar, Roopal B.

AU - Robinson, Anne M.

AU - Rosh, Joel

AU - Ruemmele, Frank M.

AU - Awni, Walid M.

PY - 2015/3/6

Y1 - 2015/3/6

N2 - Background: Adalimumab, a fully human monoclonal antibody (IgG1) 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 g/mL) compared with the low-dose (3.51 ± 2.21 g/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.

AB - Background: Adalimumab, a fully human monoclonal antibody (IgG1) 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 g/mL) compared with the low-dose (3.51 ± 2.21 g/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.

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