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


OBJECTIVE
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].
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
T
T
Dassopoulos
M C
MC
Dubinsky
J L
JL
Bentsen
C F
CF
Martin
J A
JA
Galanko
E G
EG
Seidman
R S
RS
Sandler
S B
SB
Hanauer
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001835:Body Weight; D002648:Child; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013866:Thioguanine / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
D007166:Immunosuppressive Agents; D011355:Prodrugs; D013866:Thioguanine; D001379:Azathioprine