Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.
OBJECTIVE
Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC.


METHODS
We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase.


RESULTS
At screening, 115 of 263 patients had a TC of infliximab of 3-7 μg/mL (43.7%). Of 76 patients with TCs <3 μg/mL, 69 patients (91%) achieved TCs of 3-7 μg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 μg/mL, 67 patients (93%) achieved TCs of 3-7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018).


CONCLUSIONS
Targeting patients' infliximab TCs to 3-7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.
Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven-University of Leuven, Leuven, Belgium.
Niels
N
Vande Casteele
Department of Gastroenterology, University Hospitals Leuven, KU Leuven-University of Leuven, Leuven, Belgium.
Marc
M
Ferrante
Department of Gastroenterology, University Hospitals Leuven, KU Leuven-University of Leuven, Leuven, Belgium.
Gert
G
Van Assche
Department of Gastroenterology, University Hospitals Leuven, KU Leuven-University of Leuven, Leuven, Belgium.
Vera
V
Ballet
Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven-University of Leuven, Leuven, Belgium.
Griet
G
Compernolle
Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liège, Sart-Tilman, Belgium.
Kristel
K
Van Steen
Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, KU Leuven-University of Leuven, Leuven, Belgium.
Steven
S
Simoens
Department of Gastroenterology, University Hospitals Leuven, KU Leuven-University of Leuven, Leuven, Belgium.
Paul
P
Rutgeerts
Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven-University of Leuven, Leuven, Belgium.
Ann
A
Gils
Department of Gastroenterology, University Hospitals Leuven, KU Leuven-University of Leuven, Leuven, Belgium. Electronic address: severine.vermeire@uzleuven.be.
Séverine
S
Vermeire
D000328:Adult; D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood* / Q000191:economics / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood* / Q000191:economics / Q000493:pharmacokinetics; D001530:Belgium; D003093:Colitis, Ulcerative / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics / Q000276:immunology; D003362:Cost-Benefit Analysis; D003424:Crohn Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics / Q000276:immunology; D016527:Drug Costs; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood* / Q000191:economics / Q000493:pharmacokinetics; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
Monoclonal Antibody; Personalized Medicine; Pharmacokinetics; Therapeutic Drug Monitoring