Nitisinone 2 mg · Hard-gelatin capsules

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.

The single-dose pharmacokinetics of nitisinone have been studied for nitisinone capsules in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for nitisinone capsules in healthy subjects.

Absorption — The pharmacokinetic characteristics following single oral administration of nitisinone 30 mg under fasting conditions are shown in Table 3. The multiple-dose characteristics of nitisinone 80 mg once daily are shown in Table 4. Steady-state (SS) was reached within 14 days dosing in all subjects.

* presented as median [range] — Food Effect: No food effect study was conducted with nitisinone capsules.

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

Elimination — The mean terminal plasma half-life of single dose nitisinone in healthy male subjects is 54 hours. The mean (CV%) apparent plasma clearance in 18 healthy adults following multiple once daily doses of nitisinone 80 mg is 113 (16) mL/hr.

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

Excretion: Renal elimination of nitisinone is of minor importance, since the mean of the fraction of dose excreted as unchanged nitisinone in the urine (fe(%)) was 3.0% (n=3) following multiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renal clearance of nitisinone was 0.003 L/h (25%).

Drug Interaction Studies — Nitisinone does not inhibit CYP2D6. Nitisinone is a moderate inhibitor of CYP2C9, and a weak

inducer of CYP2E1 (Table 5). Nitisinone is an inhibitor of OAT1/3 (Table 5).

↑ = Increased; ↓ = Decreased — a The interacting drug was administered alone on Day 1 and together with nitisinone on Day 17.

b Multiple doses of 80 mg nitisinone were administered daily alone from Day 3 to Day 16.

c 16 subjects in Period 2 received nitisinone and tolbutamide while 18 subjects in Period 1 received nitisinone alone.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

In vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone does not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1, OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.