Clinical Review Report: Nitisinone (Orfadin): (Sobi Canada Inc.) [Internet]

Hereditary tyrosinemia type-1 (HT-1) is a rare, autosomal recessive disorder of amino acid metabolism. The deficiency of fumarylacetoacetate hydrolase (FAH), which is the last enzyme in the pathway of tyrosine catabolism, results in the accumulation of toxic metabolites in the FAH-deficient hepatocytes and proximal renal tubular cells, and subsequently leads to liver and kidney damage. HT-1 typically manifests in infancy and is characterized by elevated plasma tyrosine levels. Liver dysfunction, such as bleeding abnormalities, hypoglycemia, ascites, edema, vomiting, irritability and jaundice, is the dominant clinical manifestation in children who are not detected by the newborn screening. Progression of the liver disease can be chronic or acute, with rapid deterioration. The lifetime risk of developing hepatocellular carcinoma (HCC) is as high as 37% in survivors without treatment, according to previous research. Many patients also suffer from neurocognitive deficits. The prevalence of HT-1 ranges from one in 12,000 to one in 100,000 individuals of Northern European descent. In Canada, a higher prevalence (one in 1,846 live births) was observed in the Saguenay–Lac-Saint-Jean region in Quebec. If untreated, the survival in patients with HT-1 is less than 12 months of life; most of these children die as a result of liver failure and severe coagulopathy.

Nitisinone (Orfadin) is a competitive inhibitor of 4-hydrooxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. It prevents the accumulation of the catabolic intermediates, which can be converted to the toxic metabolites succinylacetone (SA) and succinylacetoacetate. The effect of nitisinone on inhibiting catabolism of tyrosine also leads to an increase in plasma tyrosine levels. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent tyrosine toxicity.

Objectives: To perform a systematic review of the beneficial and harmful effects of nitisinone (capsules 2 mg, 5 mg, 10 mg, and 20 mg) for the treatment of patients with HT-1 in combination with dietary restriction of tyrosine and phenylalanine.