Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

• Published in: Clinical therapeutics 2011-07, Vol.33 (7), p.946-964
• Main Authors: Fasanmade, Adedigbo A., PhD, Adedokun, Omoniyi J., MS, Blank, Marion, PhD, Zhou, Honghui, PhD, Davis, Hugh M., PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age Factors; Aged; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Child; Clinical trials; Clinical Trials, Phase III as Topic; Crohn Disease - drug therapy; Crohn's disease; Disease; Drug therapy; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Agents - pharmacokinetics; Gastrointestinal Agents - therapeutic use; Half-Life; Humans; Infliximab; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; Models, Biological; monoclonal antibody; Nonlinear Dynamics; Other diseases. Semiology; pediatric; Pharmaceutical industry; Pharmacology. Drug treatments; population pharmacokinetics; Retrospective Studies; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Tissue Distribution; Tumor Necrosis Factor-alpha - antagonists & inhibitors; tumor necrosis factor-α; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2011.06.002

Abstract Background Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. Objectives The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohn's disease (CD) from 2 Phase III studies. Methods This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6–76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease] and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. Results Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; Vd in the central compartment (V1 ), 54.2 (1.15) mL/kg; Vd in the peripheral compartment (V2 ), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V1 , 52.7 (0.49) mL/kg; V2 , 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V2 decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trou