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].

Trial registration: ClinicalTrials.gov NCT00113503.

FIGURE 1

Azathioprine dosing in the two arms

FIGURE 2

Flow of patients

FIGURE 3

Scatter plot, mean values and 95% confidence intervals for the 6TGN and 6MMPR concentrations in individual subjects by TPMT activity in the individualized dosing arm ( ) and in the weight-based arm (Δ) (per protocol analysis). A: 6TGN concentrations in normal metabolizers. B: 6MMPR concentrations in normal metabolizers. C: 6TGN concentrations in intermediate metabolizes. D: 6MMPR concentrations in intermediate metabolizes.

FIGURE 4

Scatter plot, median values and interquartile ranges of the 6TGN concentrations at week 16 in the per-protocol remitters (n=12) and non-remitters (n=14). Median 6TGN concentrations were 216 and 149 pmol/8 x 10⁸ RBCs in remitters and non-remitters respectively (p=0.07). [Note: There were 15 non-remitters at week 16, but 6TGN data were missing for one subject with normal TPMT activity in the individualized dosing arm. At week 12, this subject had TGN and 6MMP concentrations of 198 and 2633 pmol/8 x 10⁸ RBCs respectively.]