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Mechanism of Action
Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.
Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine [see WARNINGS AND PRECAUTIONS].
Limited information exists on the metabolism, distribution, and excretion of nitisinone in rats. Nitisinone was greater than 90% bioavailable following oral administration of the labeled compound in rats and was distributed to different organs, particularly the liver and kidney, where radioactivity remained for 7 days after administration. Nitisinone was bio-transformed in rats and excreted via the urine.
No pharmacokinetic studies of nitisinone have been conducted in children or HT-1 patients.
The single-dose pharmacokinetics of nitisinone have been studied in ten healthy male volunteers aged 19-39 years (median 32 years). Nitisinone, 1 mg/kg body weight, was administered as a capsule and a liquid. The median time for maximum plasma concentration was 3 hours for the capsule and 15 minutes for the liquid. The capsule and liquid formulation were found to be bioequivalent based on an analysis of area under the plasma concentration-time curve and maximum plasma concentration (Cmax).
No information on the metabolism of nitisinone in humans is available. The mean terminal plasma half-life of nitisinone in healthy male volunteers was 54 hours. The effect of food on the pharmacokinetics of nitisinone has not been studied.
Animal Toxicology and/or Pharmacology
In pregnant mice given oral gavage doses of 5, 50, 250 mg/kg/day from gestation day 7 through 16, incomplete skeletal ossification of fetal bones was observed with doses of ≥ 5 mg/kg/day. In pregnant mice given the same doses from gestation day 7 through weaning, gestation length increased in animals given ≥ 50 mg/kg/day. Decreased pup survival by 9% compared to 5% in untreated controls was observed at 5 mg/kg/day.
In pregnant rabbits given oral gavage doses of 5, 12, 25 mg/kg/day from gestation day 7 through 19, maternal toxicity and incomplete skeletal ossification of fetal bones was observed with doses of ≥ 5 mg/kg/day.
Clinical Studies in HT-1
The efficacy and safety of Orfadin in patients with HT-1 were evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with Orfadin at a starting dose of 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.
In this clinical study, for patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting between 2 and 6 months of age who were treated with dietary restrictions and nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients treated with dietary restriction alone had 2- and 4year survival probabilities of 74% and 60%, respectively.
The effects on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.
Urine succinylacetone was measured in 186 patients. In all 186 patients, urinary succinylacetone level decreased to less than 1 mmol/mol creatinine. The median time to normalization was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 μmol/L (95% confidence interval: 23-51 μmol/L). Plasma succinylacetone was measured in 172 patients. In 150 patients (87%), plasma succinylacetone decreased to less than 0.1 μmol/L. The median time to normalization was 3.9 months.
Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.
Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 g/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 g/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 g/mol creatinine (reference value for age ≤ 12 g/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1microglobulin levels decreased from 2.8 to 2.0 g/mol creatinine (reference for age ≤ 6 g/mol creatinine).
The long term effect of nitisinone with regard to hepatic function in patients was not assessed.
Last reviewed on RxList: 3/1/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Orfadin Information
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