Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria

Abstract

Alkaptonuria is an autosomal recessive disease involving a deficiency of the enzyme homogentisate dioxygenase, which is involved in the tyrosine degradation pathway. The enzymatic deficiency results in high concentrations of homogentisic acid (HGA), which results in orthopedic and cardiac complications, among other symptoms. Nitisinone (NTBC) has been shown to effectively treat alkaptonuria by blocking the conversion of 4-hydroxyphenylpyruvate to HGA, but there have been concerns that using doses higher than about 2 mg/day could cause excessively high levels of tyrosine, resulting in crystal deposition and corneal pathology. We have enrolled seven patients in a study to determine whether higher doses of NTBC were effective at further reducing HGA levels while maintaining tyrosine at acceptable levels. Patients were given varying doses of NTBC (ranging from 2 to 8 mg/day) over the course of between 0.5 and 3.5 years. Urine HGA, plasma tyrosine levels, and plasma NTBC were then measured longitudinally at various doses. We found that tyrosine concentrations plateaued and did not reach significantly higher levels as NTBC doses were increased above 2 mg/day, while a significant drop in HGA continued from 2 to 4 mg/day, with no significant changes at higher doses. We also demonstrated using untargeted metabolomics that elevations in tyrosine from treatment resulted in proportional elevations in alternative tyrosine metabolic products, that of N-acetyltyrosine and γ-glutamyltyrosine.

Nitisinone: a review

“…13,24,25,[101][102][103][104] The drop in HGA concentrations was rapid, with approximately 60% decrease in circulating HGA within 48 hours on 2 mg dose (unpublished data), and thus is an efficacious treatment. 101 Six clinical trials have been undertaken on the use of nitisinone to treat AKU.…”

“…101 Six clinical trials have been undertaken on the use of nitisinone to treat AKU. 24,25,86,[102][103][104] The first study was an early dose ranging study in two older women with AKU. 102 An open-label, single-center study of 9 AKU patients showed that the dose required to decrease HGA significantly was up to 30-fold lower than that used in treating HT1.…”

“…On the contrary, Gertsman et al revealed a significant decrease in urine HGA level in 7 AKU patients when the nitisinone dose was increased from 2 to 4 mg/day, with no significant changes at higher doses. 104 Despite the dosage to treat AKU is lower than that to treat HT1, it still causes accumulation of Tyr over the recommended threshold of 400-500 µmol/L with a large interindividual variability, and long-term monitoring of plasma Tyr levels is needed because the metabolic fate of this is largely unknown in AKU. 13,24,25,[102][103][104] It is postulated that treatment with nitisinone should be started as early as possible before renal functions decline and other potentially fatal acute complications develop.…”

“…104 Despite the dosage to treat AKU is lower than that to treat HT1, it still causes accumulation of Tyr over the recommended threshold of 400-500 µmol/L with a large interindividual variability, and long-term monitoring of plasma Tyr levels is needed because the metabolic fate of this is largely unknown in AKU. 13,24,25,[102][103][104] It is postulated that treatment with nitisinone should be started as early as possible before renal functions decline and other potentially fatal acute complications develop. 99,100 Nitisinone and neuroblastoma Neuroblastoma, the most common solid neoplasm of childhood outside of the central nervous system, is a neural crest-derived neoplasm.…”

“…13,24,25,[102][103][104] Still, all patients taking nitisinone should adhere to a phenylalanine-and Tyr-restricted diet to minimize the tyrosinemia produced by the compound.…”