July 27, 2016
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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 5aminolevulinate, 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].


No pharmacokinetic studies of nitisinone have been conducted in children or HT-1 patients. The single-dose pharmacokinetics of nitisinone have been studied for both ORFADIN capsules and ORFADIN oral suspension in healthy subjects.


Following administration of ORFADIN 30 mg under fasting conditions, the peak serum nitisinone concentration (Cmax) occurred at approximately 3.5 hours postdose for the capsules and 0.38 hours postdose for the oral suspension. The pharmacokinetic parameters are shown in Table 2.

TABLE 2 : Nitisinone Geometric Mean Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral Dose of ORFADIN Under Fasting Conditions

Treatment C max (micromol/L) [range] tmax* (h) [range] AUC72h (micromol•h/L) [range]
ORFADIN capsule (n=12) 10.2
[8.03 to 18.0]
[0.75 to 8.00]
[315 to 500]
ORFADIN oral suspension (n=12) 9.74
[7.78 to 20.3]
[0.25 to 4.00]
[264 to 456]
* presented as median [range]

Food Effect: No food effect study was conducted with ORFADIN capsules. For ORFADIN oral suspension, a high calorie (800 to 1000 calories) and high fat meal

(approximately 50% of total caloric content) did not affect nitisinone total exposure (AUC72h), but decreased the Cmax by approximately 20% [see DOSAGE AND ADMINISTRATION].


In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration.


The mean terminal plasma half-life of nitisinone in healthy male subjects is 54 hours.

Excretion: Not known.

Metabolism: In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

Drug Interaction Studies

Based on in vitro studies, there is a potential for nitisinone to inhibit CYP2C9 [see DRUG INTERACTIONS]. Nitisinone is not expected to inhibit CYP 1A2, 2C19, or 3A4 based on in vitro studies. The potential for nitisinone to inhibit CYP2D6 and CYP2E1 at the recommended dosage is unknown due to limited data.

Clinical Studies

The efficacy and safety of ORFADIN in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 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 (i.e. 0.3 to 0.5 mg/kg twice daily), and the dose was increased in some patients to 2 mg/kg/day (i.e. 1 mg/kg twice daily) 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 4year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients treated with dietary restriction alone had 2-and 4-year 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 micromol/L (95% confidence interval: 23, 51 micromol/L). Plasma succinylacetone was measured in 172 patients. In 150 patients (87%), plasma succinylacetone decreased to less than 0.1 micromol/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 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/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 grams/mol creatinine (reference value for age less than or equal to12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine).

The long term effect of nitisinone on hepatic function was not assessed.

Last reviewed on RxList: 6/21/2016
This monograph has been modified to include the generic and brand name in many instances.

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