Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.

Abstract

BACKGROUND:

Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD).

AIM:

To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations.

METHODS:

This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day.

RESULTS:

After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07).

CONCLUSIONS:

Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

• Authors: T Dassopoulos, M C Dubinsky, J L Bentsen, C F Martin, J A Galanko, E G Seidman, R S Sandler, S B Hanauer
• Journal: Alimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 39 Issue 2 Pg. 163-75 (Jan 2014) ISSN: 1365-2036 [Electronic] England
• PMID: 24237037 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Immunosuppressive Agents
• Prodrugs
• Thioguanine
• Azathioprine

Topics

• Adolescent
• Adult
• Azathioprine (administration & dosage, adverse effects, therapeutic use)
• Body Weight
• Child
• Crohn Disease (blood, drug therapy)
• Double-Blind Method
• Female
• Humans
• Immunosuppressive Agents (administration & dosage, adverse effects, therapeutic use)
• Male
• Prodrugs (administration & dosage, adverse effects, therapeutic use)
• Thioguanine (blood)
• Treatment Outcome
• Young Adult