title: Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study.
abstract: BACKGROUND
  Infliximab (IFX) is effective therapy for ulcerative colitis and Crohn's disease, but it may be associated with side effects and loss of response. One loss of response mechanism is increased IFX clearance (IFX-CL), resulting in short half-life and decreased troughs.
  
  
  METHODS
  Patients were recruited, and relevant demographic, clinical, and laboratory data were recorded. IFX serum concentrations and antibodies against IFX (ATI) were measured for therapeutic drug monitoring and modeled using NONMEM.
  
  
  RESULTS
  There were 169 IFX concentrations (Crohn's disease = 73, ulcerative colitis = 92, and diagnosis undetermined = 4). Patient factors significantly associated with high IFX-CL were low albumin, high body weight, and the presence of ATI (P ≤ 0.001). Disease type did not affect IFX-CL. The typical IFX-CL was 0.381 L/d. ATI formation was associated with a 259% increase in IFX-CL. The estimated median IFX effective half-life was 5.6 ± 2.4 days. Patients with low weight are more likely to have low troughs because IFX CL is not linearly related to weight, but IFX dosing is weight-based (in mg/kg). Simulations investigating alternative dose strategies suggested that more reliably measurable concentrations over the dose interval were achieved when the dose interval was shortened than by increasing administered dose.
  
  
  CONCLUSIONS
  IFX-CL is significantly influenced by patient factors, specifically, albumin, body weight, and ATI. There should be a decreasing IFX dose interval strategy, particularly for low albumin patients. Higher starting doses may benefit low body weight patients. Pharmacokinetic models and therapeutic drug monitoring may ensure that patients maintain measurable concentrations throughout dose intervals. Individualized dosing may improve outcomes for IFX-treated patients with Crohn's disease and ulcerative colitis.
authors.affiliation: *IBD Center, Department of Gastroenterology and Liver Diseases and the Research Center for Digestive Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and ‡Projections Research Inc., Springview Lane Phoenixville, Phoenixville, Pennsylvania.
authors.forename: Iris
authors.initials: I
authors.lastname: Dotan
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ron
authors.forename: Henit
authors.initials: H
authors.lastname: Yanai
authors.forename: Stuart
authors.initials: S
authors.lastname: Becker
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
authors.forename: Lior
authors.initials: L
authors.lastname: Yahav
authors.forename: Merav
authors.initials: M
authors.lastname: Ben Yehoyada
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000453:epidemiology*; D000069285:Infliximab; D007557:Israel / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D016544:Patient Simulation; D011379:Prognosis; D011446:Prospective Studies; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D000069285:Infliximab