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Early increases in 6-MMPR predicts thiopurine-induced hepatotoxicity in IBD patients

Patients with inflammatory bowel disease treated with thiopurines had a higher risk for hepatotoxicity if they had elevated 6-methylmercaptopurine ribonucleotide metabolite levels at 1 week after treatment began, according to recent study data.

This finding, along with independent risk factors such as age, sex and BMI, could enable personalized thiopurine treatment to prevent early failure in IBD patients, Dennis R. Wong, PharmD, PhD, of the department of clinical pharmacy, pharmacology and toxicology at Zuyderland Medical Center in the Netherlands, and colleagues concluded.

Dennis R. Wong

“Thiopurine metabolism in humans is complex due to involvement of various metabolic enzymes and the occurrence of dose-dependent adverse reactions is therefore unpredictable,” Wong told Healio.com/Hepatology. “Since alternative therapeutic options are limited in IBD, early identification of patients at risk of thiopurine-related intolerable adverse reactions is important.”

Wong and colleagues evaluated the first 270 consecutive patients enrolled in the TOPIC trial (153 women; median age, 40 years), who were randomly assigned to standard thiopurine treatment or tailored thiopurine regimens based on a thiopurine S-methyltransferase genotypes. They evaluated blood samples for metabolite levels 1 week after thiopurine treatment began, and defined hepatotoxicity as alanine aminotransaminase levels above twice the upper limit of normal, or a ratio of alanine aminotransaminase to alkaline phosphatase of five or more.

During the first 20 weeks of treatment, 17% of patients had hepatotoxicity (median, 4 weeks), which occurred more frequently in patients treated with mercaptopurine vs. azathioprine (OR = 2.1; 95% CI, 1.1-4.1).

Analysis of 174 patients who were on a stable dose of thiopurine showed that those who exceeded a 6-MMPR threshold of 3,615 pmol/8 x 10⁸ erythrocytes at 1 week had a significantly increased risk for hepatotoxicity (OR = 3.8; 95% CI, 1.8-8). They also had an increased risk for GI complaints (OR = 2.4; 95% CI, 1.4-4.3) and general malaise (OR = 2; 95% CI, 1.1-3.7).

In addition, age, male sex and BMI were independently predictive of hepatotoxicity.

Based on these findings, the researchers developed a predictive algorithm to assess the risk for hepatotoxicity (area under the curve = 0.83; 95% CI, 0.75-0.91).

“In this prospective study, we developed for the first time an accurate prediction model for thiopurine-induced hepatotoxicity, based on 6-MMPR metabolite concentrations assessed at week one and the significant patient-related determinants age, gender and BMI,” the researchers concluded. “Thiopurine-associated hepatotoxicity occurred in more than 80% of the cases during the first 8 weeks of treatment and strongly correlated with thiopurine withdrawal and/or reduction in thiopurine dose.”

“Considering the patient-related risk factors (i.e. age, male gender and BMI), T1 metabolite measurement may help the clinician to identify the patients at risk,” Wong said. “Of course, this should be validated in clinical practice. In my opinion, optimal dosing is essential and should become a target to improve prolonged efficacy and safety of thiopurine therapy. I hope that a more personalized approach may prevent unnecessary failure of thiopurines in the future.” – by Adam Leitenberger

Disclosures: The researchers report no relevant financial disclosures.

Editor's note: This article was updated on February 28 with additional comments from the study author.