Allopurinol lowers hepatotoxicity risk in thiopurine users

Use of allopurinol results in a 58-percent reduced risk of hepatotoxicity among thiopurine users, while myelotoxicity rates are not affected, according to a study. Moreover, thiopurine persistence is extended by 2.1 years in allopurinol users.

“Individuals on allopurinol continued their thiopurine therapy for more than twice the length of time, and combined thiopurine toxicity was reduced by 13 percent,” the researchers said. “These results support the safety of concomitant use of allopurinol in individuals dependent on thiopurine therapy.”

This retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Co-use of allopurinol was compared to nonuse among these patients. The researchers then derived hazard ratios (HRs) for hepatotoxicity, myelotoxicity, and pancreatitis using time-dependent Cox proportional hazards models, adjusted for potential confounders. Log-ran statistics was used to assess the persistence of thiopurine use.

A total of 37,360 thiopurine users were identified, of which 1,077 were concomitantly taking allopurinol. Risk of hepatotoxicity decreased by 58 percent in those concomitantly taking allopurinol (HR, 0.42, 95 percent confidence interval [CI], 0.30–0.60; number needed to treat [NNT], 46). [Br J Clin Pharmacol 2021;87:2333-2340]

Myelotoxicity rate was not affected by co-use of allopurinol (HR, 0.96, 95 percent CI, 0.89–1.03). On the other hand, pancreatitis risk increased (HR, 3.00, 95 percent CI, 1.01–8.93; number needed to harm, 337), but this was only observed among patients with active gout, suggesting confounding by indicators.

Notably, allopurinol co-users maintained thiopurine therapy more than twice as long as those not using allopurinol (3.9 vs 1.8 years; p<0.0001).

These findings were consistent with those from three studies with smaller sample sizes. The first one reported hepatotoxicity resolution in 11 of 14 patients (79 percent) taking allopurinol. The other studies demonstrated similar results: 82 percent and 83 percent of patients eliminated hepatotoxicity after initiating allopurinol with concurrent thiopurine use, respectively. [Therap Adv Gastroenterol 2017;10:819‐827; Inflamm Bowel Dis 2016;22:1639‐1646; Aliment Pharmacol Ther 2008;28:734‐741]

“However, these studies tested this beneficial effect of allopurinol in a clinical setting,” the researchers said. “Moreover, these studies lacked a comparator group (ie, it is unclear whether hepatotoxicity would have resolved without allopurinol).”

These results could be potentially explained by the pharmacokinetic interaction between allopurinol and thiopurines. High blood levels of 6‐methylmercaptopurine (6-MMPR) correlated with a higher risk of hepatotoxicity, while low blood concentrations of 6‐thioguanine nucleotides (6-TGN) were associated with poor therapeutic response. [Gastroenterology 2006;130:1047‐1053; Gastroenterology 2000;118:705‐713]

“Allopurinol increases 6‐TGN levels at the expense of 6‐MMPR exposure. This should translate into better clinical outcomes (eg, lower risks of hepatotoxicity and higher therapy persistence), and we here demonstrate this in a large outpatient setting,” the researchers said. [Aliment Pharmacol Ther 2005;22:441‐446; J Crohns Colitis 2009;3:162‐167; J Gastroenterol Hepatol 2011;26:49‐54]

“Current guidelines … state that the thiopurine dose should be reduced by 66–75 percent when concomitantly using allopurinol. The usual dose of allopurinol used for this purpose is 100 mg/day,” they noted.