Safety and efficacy of personalized versus standard initial dosing of thiopurines: Systematic review and meta-analysis of randomized trials

ABSTRACT

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:

• Genotype
• Azathioprine
• 6-mercaptopurine
• Cytopenia
• Inflammatory bowel disease
• Crohn’s disease
• Ulcerative colitis
• Immune-mediated inflammatory disease

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

A Jena: Manuscript writing, Screening and selection, Manuscript review and approval. CL Birda: Screening and Selection, Data extraction, RoB Manuscript review and approval. A Choudhury: Screening and Selection, Data extraction, RoB, Manuscript review and approval. V Sharma: Conception, Data validation, RoB, Analysis, Manuscript review and approval. AJ and CLB are equal first authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2236554

Additional information

Funding

This paper was not funded.