Simultaneous succinylacetone-nitisinone measurement in tyrosinemia type I patients and evaluation of nitisinone therapeutic range

Abstract

Abstract Introduction: In tyrosinemia type I (HT1) accumulation of succinylacetone causes severe hepatic and renal dysfunction and hepatocellular carcinoma, and the only drug used in the treatment is nitisinone (NTBC). While succinylacetone measurement from dried blood spots (DBS) is used in the diagnosis of patients, simultaneous measurements of succinylacetone and NTBC are preferred in the treatment follow-up. The aim of this study was to evaluate the results of simultaneous LC-MS/MS analysis of succinylacetone and NTBC in HT1 patients. We also evaluated the plasma/DBS ratio and the upper therapeutic range for NTBC. Materials and method: Plasma and DBS samples from HT1 patients were used for succinylacetone and NTBC analyses and LC-MS/MS was used for simultaneous measurements of both of them. Results: The plasma/DBS ratio for NTBC was 1.92. The succinylacetone level, which was determined as the treatment goal, was suppressed (< 1 nmol/L) with the use of NTBC in 95.6% (109/114) of the cases. However, NTBC level was found above the therapeutic upper limit in 64.7% of these cases. Conclusion: The suppression rate of succinylacetone, which is one of the treatment targets for HT1, is high with 95.6%. However, the recommended therapeutic upper limit for NTBC was exceeded in 64.7% of the patients. It is also important to calculate the plasma/DBS NTBC ratio in laboratories analysing NTBC from DBS and to evaluate the therapeutic range targets according to this ratio. Evaluation of an individualized dose with a review of the therapeutic target may be considered in longitudinal studies examining clinical outcomes.