title: Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis.
abstract: OBJECTIVE
  The pharmacokinetics of infliximab during induction treatment for ulcerative colitis (UC) have not been studied. We investigated serum concentrations of infliximab and the early appearance of antibodies to infliximab (ATI) during induction treatment in patients with moderate-to-severe UC.
  
  
  METHODS
  We performed a prospective analysis of 19 consecutive patients with moderate-severe UC (endoscopic Mayo ≥ 2) receiving induction therapy with infliximab (5 mg/kg at weeks 0, 2, and 6) at 2 centers in Amsterdam, The Netherlands, from July 2012 through March 2014. Serial serum and fecal samples were collected for 6 weeks and concentrations of infliximab, ATI, c-reactive protein (CRP), albumin, and fecal calprotectin were measured. Treatment success was defined as endoscopic response (≥ 1 point reduction in the endoscopic Mayo score) at week 8.
  
  
  RESULTS
  Eleven patients (58%) had an endoscopic response. The median serum concentrations of infliximab at week 6 were 8.1 μg/mL in responders (interquartile range, 3.0-13.7 μg/mL) and 2.9 μg/mL in nonresponders (interquartile range, 0.01-5.8 μg/mL) (P = .03). ATIs were detected in 7 patients as early as day 18 (median, 28 d; interquartile range, 18-42 d). Six of the 8 nonresponders tested positive for ATIs vs 1 of 11 responders (P < .01; odds ratio, 30.0; 95% CI, 2.2-406.2). Patients with a baseline concentration of CRP greater than 50 mg/L had lower drug exposure from weeks 0 to 6 (587 mg/L/d in patients with high levels of CRP vs 1361 mg/L/day in patients with low CRP; P = .001). The median area under the curve for serum concentration of infliximab during induction therapy was 1230 mg/L/d in nonresponders vs 1352 mg/L/d in responders (P = .65).
  
  
  CONCLUSIONS
  There is a significant difference in serum concentration of infliximab at week 6 of treatment between responders and nonresponders. Early development of ATIs during induction therapy reduces the serum concentration of infliximab and is associated with nonresponse to treatment. Patients with high baseline serum levels of CRP had lower serum concentrations of infliximab.
  
  
  BACKGROUND
  NL39626.018.12.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannan F
authors.initials: JF
authors.lastname: Brandse
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Mathôt
authors.affiliation: Biologicals Laboratory, Sanquin Laboratory, Amsterdam, The Netherlands.
authors.forename: Desiree
authors.initials: D
authors.lastname: van der Kleij
authors.affiliation: Sanquin Research, Sanquin Laboratory, Amsterdam, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Yaël
authors.initials: Y
authors.lastname: Ashruf
authors.affiliation: Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Jeroen M
authors.initials: JM
authors.lastname: Jansen
authors.affiliation: Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Svend
authors.initials: S
authors.lastname: Rietdijk
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Löwenberg
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.affiliation: Prometheus Laboratories, San Diego, California.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: g.dhaens@amc.uva.nl.
authors.forename: Geert R
authors.initials: GR
authors.lastname: D'Haens
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D000069285:Infliximab / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D009426:Netherlands; D011446:Prospective Studies; D044967:Serum / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D007155:Immunologic Factors; D000069285:Infliximab
keywords: Anti-TNF; IBD; Response to Treatment; Tumor Necrosis Factor