Background: Pretherapy assessment of specific genetic polymorphism (TPMT, NUDT15, FTO, RUNX1, etc) or enzyme levels (for TPMT) may help personalize the dose of thiopurines and avoid adverse effects.
Research design and methods: A systematic review of randomized controlled trials (RCTs) comparing personalized versus standard strategy for initial thiopurine dosing was performed. The electronic databases were searched on 27 September 2022. The outcomes were overall adverse effects, myelotoxicity, drug interruptions, and therapeutic efficacy with either strategy. The certainty of evidence was assessed using GRADE methodology.
Results: We included six randomized trials, done dominantly in patients with inflammatory bowel disease (IBD). The personalized strategies were genotype testing in 4 trials (TPMT in three trials, NUDT15 in two) and enzyme levels for TPMT in two trials. The pooled risk of myelotoxicity in personalized dosing was lower [RR = 0.72 (95%CI, 0.55-0.94, I2 = 0%)]. The pooled risk of pancreatitis (RR = 1.10I, 0.78-1.56, I2 = 0%), hepatotoxicity (RR = 1.13, 0.69-1.88, I2 = 45), and GI intolerance (RR = 1.01, 0.92-1.10, I2 = 0) were similar in two groups. The pooled risk of drug interruption in individualized dosing was similar to the standard dosing group (RR = 0.97, I2 = 68%).
Conclusion: Personalized testing-based initial thiopurine dosing is protective against myelotoxicity as compared to standard weight-based dosing.
Keywords: 6-mercaptopurine; Azathioprine; Crohn’s disease; Cytopenia; Genotype; Immune-mediated inflammatory disease; Inflammatory bowel disease; Ulcerative colitis.