Nitisinona

Uses

Nitisinona is a hydroxyphenylpyruvate dioxygenase inhibitor used as an adjunct to dietary restrictions for the treatment of hereditary tyrosinemia type 1 (HT-1), which causes intolerance to tyrosine containing foods.

Used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Nitisinona is also used to associated treatment for these conditions: Hereditary tyrosinemia type-1

How Nitisinona works

Nitisinona is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolyase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.

Toxicity

Side effects include elevated plasma levels of this amino acid, hepatic and liver failure.

Food Interaction

• Limit the intake of phenylalanine and tyrosine.
• Take separate from meals. Nitisinona capsules should be separated by one hour before or two hours after meals.
• Take with or without food. Nitisinona tablets can be taken with or without food but food may prolong the Tmax by six hours.

[Moderate] MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4.

Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

Orange juice is not expected to interact with these drugs.

Nitisinona Drug Interaction

Moderate: sulfamethoxazole / trimethoprim, diltiazemUnknown: charcoal, ubiquinone, copper gluconate, glucose, glycerin, heparin, sodium iodide, arginine, levocarnitine, cysteine, lithium, metoprolol, metoprolol, acetaminophen, bioflavonoids, vitamin a topical, bioflavonoids, sotalol

Nitisinona Disease Interaction

Moderate: leukopenia/thrombocytopenia

Elimination Route

The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).

Half Life

~54 hours

Innovators Monograph

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