Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease.
OBJECTIVE
To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.


METHODS
Patients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.


RESULTS
Two hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P < 0.001). The ITPA 94C>A mutation was associated with withdrawal due to flu-like symptoms (P = 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmo/h/mg/Hb (81% vs. 43% respectively, P < 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P = 0.0017).


CONCLUSIONS
TPMT testing predicts adverse effects and reduced chance of clinical response (TPMT >35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.
Ansari
A
A
Department of Gastroenterology, St Thomas' Hospitals Foundation, NHS Trust, London, UK.
Arenas
M
M
Greenfield
S M
SM
Morris
D
D
Lindsay
J
J
Gilshenan
K
K
Smith
M
M
Lewis
C
C
Marinaki
A
A
Duley
J
J
Sanderson
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D007166:Immunosuppressive Agents; D013873:Thionucleotides; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine