Introduction Many patients, particularly those with high thiopurine methyltransferase (TPMT) activity, preferentially methylate thiopurine drugs, resulting in high levels of methylated metabolites and low thioguanine nucleotides (TGNs). This metabolite pattern is associated with hepatotoxicity and non-response to treatment. Co-prescription of thiopurines (at 25–50% of standard dose) with allopurinol, (which blocks xanthine oxidase) appears to circumvent this problem, optimising both metabolite profile and clinical outcome.
Data on the use of allopurinol and thiopurines remain limited. We previously reported our experience of using this combination in thiopurine-related hepatotoxicity. In this study we report further experience for a broader indication, including toxicity (mainly hepatic) non-response with adverse metabolite profile, and very high TPMT activity.
Methods Patients prescribed combination treatment were identified from notes in the IBD clinic, TGN monitoring results and hospital pharmacy records. Data were collected retrospectively. We were particularly interested in whether combination treatment overcame the specific problem that precluded thiopurine monotherapy. We also analysed changes in metabolite profiles and subsequent clinical outcome.
Results 35 patients have been co-prescribed allopurinol and thiopurines since our previous report. 20 had Crohn's disease and 15 ulcerative colitis, age range 20–65 years. Their average TPMT activity was 40 pmol/h/mgHb, (vs 32.5 in our population overall).
In those receiving co-prescription for adverse effects (14 hepatotoxicity and three other: rash, nausea, fatigue) 94% were able to tolerate combination treatment with complete resolution of liver function tests abnormalities where relevant, of these 88% achieved clinical remission. In 10 patients failing thiopurine monotherapy 50% achieved clinical response on combination treatment. In eight started on combination treatment as primary therapy six (75%) achieved remission, comparing favourably with historical controls. The only adverse event was a transient lymphopaenia in a patient that had mistakenly continued full dose thiopurine.
TGN levels increased from an average of 192 to 449 pmol/8×108 RBC on co-treatment, while methylmercaptopurine levels decreased from an average of 503 pmol/8×108 RBC on single agent treatment to just 16 on combination therapy.
Conclusion Combination treatment with reduced-dose thiopurine and allopurinol circumvents predominant methylation, optimising metabolite profiles, avoiding hepatotoxicity and improving clinical response. Using combination treatment as first line should lead to a faster remission in those with high TPMT activity. Allopurinol co-prescription may also overcome other side effects. Whether combination therapy should be used first-line in those with high TPMT activity, or more extensively, warrants further investigation in a prospective trial.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.