Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism.
BACKGROUND
Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy.


OBJECTIVE
To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism.


METHODS
A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8)  erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications.


RESULTS
A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8)  erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8)  erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy.


CONCLUSIONS
Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.
Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Shih
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Nguyen
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Zheng
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P
Ibanez
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L
Mei
L Y
LY
Kwan
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K
Bradford
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C
Ting
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Targan
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Vasiliauskas
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
D007166:Immunosuppressive Agents; C010240:6-methylthiopurine; D015122:Mercaptopurine; D001379:Azathioprine