Nitisinone

Usage

• Nitisinone is prescribed for the treatment of hereditary tyrosinemia type 1 (HT-1), a rare genetic disorder affecting tyrosine metabolism. It is used in conjunction with dietary restrictions of tyrosine and phenylalanine. Nitisinone is also indicated for the treatment of alkaptonuria (AKU) in adults.
• Pharmacological Classification: Enzyme inhibitor (4-hydroxyphenylpyruvate dioxygenase inhibitor).
• Mechanism of Action: Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase, which is involved in the breakdown of tyrosine. In HT-1, this inhibition prevents the accumulation of toxic metabolites, specifically succinylacetone, which causes liver and kidney damage. In AKU, it reduces the production of homogentisic acid, which is responsible for the symptoms of the disease.

Alternate Names

• International Nonproprietary Name (INN): Nitisinone.
• Brand Names: Orfadin, Nityr.

How It Works

• Pharmacodynamics: By inhibiting 4-hydroxyphenylpyruvate dioxygenase, nitisinone prevents the formation of toxic metabolites like succinylacetone in HT-1 and reduces homogentisic acid production in AKU. This leads to improved liver and kidney function in HT-1 patients and reduces ochronosis and other symptoms in AKU patients.

• Pharmacokinetics:

  • Absorption: Nitisinone is well-absorbed orally.
  • Metabolism: It undergoes hepatic metabolism, but specific pathways and enzymes involved are not fully characterized.
  • Elimination: Primarily excreted in the urine, with a small portion eliminated in feces.

• Mode of Action: Nitisinone acts as a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase. This enzyme is crucial in the tyrosine catabolic pathway. Inhibition occurs at the molecular level by binding to the enzyme’s active site.

• Elimination Pathways: Primarily renal excretion, with minor hepatic elimination. Limited information on CYP enzyme involvement.

Dosage

Standard Dosage

Adults:

• Starting dose: 1 mg/kg body weight orally once daily.
• Dose adjustment: Titrate based on succinylacetone levels in urine and/or plasma. Increase to 1.5 mg/kg/day if succinylacetone is still detectable after one month. Maximum dose: 2 mg/kg/day.

Children:

• Starting dose: 1 mg/kg body weight orally once daily. For children weighing less than 20 kg, divide the total daily dose into two administrations.
• Dose adjustment: As with adults, titrate based on succinylacetone levels. Maximum dose: 2 mg/kg/day.

Special Cases:

• Elderly Patients: No specific dose adjustments are generally required.
• Patients with Renal Impairment: No specific dose adjustments are indicated, although caution is advised.
• Patients with Hepatic Dysfunction: No specific dose adjustments are outlined, but use with caution.
• Patients with Comorbid Conditions: Consider individual patient factors.

Clinical Use Cases

Nitisinone’s primary use is chronic management of HT-1 and AKU. It is not typically used in acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Dosage adjustments in such scenarios are not relevant to nitisinone’s clinical application.

Dosage Adjustments

Dosage modifications are based primarily on urine/plasma succinylacetone levels, with a maximum dose of 2 mg/kg/day. Dose adjustment based on renal or hepatic impairment isn’t routinely required, but careful monitoring is recommended. Genetic polymorphism information relating to drug metabolism is limited.

Side Effects

Common Side Effects

• Leukopenia, thrombocytopenia, corneal keratopathy, conjunctivitis.

Rare but Serious Side Effects

• Severe thrombocytopenia, liver failure (in patients with HT-1 if nitisinone is discontinued abruptly).

Long-Term Effects

• Potential for cataracts with prolonged use.

Adverse Drug Reactions (ADR)

• Exfoliative dermatitis, Stevens-Johnson syndrome (rare but serious).

Contraindications

• Hypersensitivity to nitisinone or any component of the formulation.

Drug Interactions

• Limited information available on clinically significant drug interactions. Closely monitor patients on concomitant medications, especially those metabolized by the liver.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Data limited. Potential benefits may outweigh risks in some cases, especially for HT-1 management.
• Breastfeeding: It is unknown if nitisinone is excreted in human milk. Advise women to exercise caution.

Drug Profile Summary

• Mechanism of Action: Inhibits 4-hydroxyphenylpyruvate dioxygenase, preventing accumulation of toxic metabolites.
• Side Effects: Leukopenia, thrombocytopenia, corneal keratopathy, conjunctivitis, rarely severe thrombocytopenia.
• Contraindications: Hypersensitivity.
• Drug Interactions: Limited data available.
• Pregnancy & Breastfeeding: Limited data, potential benefits may outweigh risks in some cases.
• Dosage: 1 mg/kg/day, adjusted based on succinylacetone levels; Max. 2 mg/kg/day.
• Monitoring Parameters: Urine/plasma succinylacetone, liver function tests, alpha-fetoprotein levels, complete blood count.

Popular Combinations

• Nitisinone is generally used as monotherapy for HT-1 and AKU, although dietary restriction of tyrosine and phenylalanine is essential in HT-1 management. No other specific drug combinations are routinely recommended.

Precautions

• General Precautions: Monitor hematological parameters, liver function, and ophthalmological status regularly.
• Specific Populations: Careful monitoring during pregnancy and breastfeeding. No specific precautions for elderly or menstruating individuals related to nitisinone use.
• Lifestyle Considerations: No specific lifestyle restrictions identified.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Nitisinone?

A: The starting dose is 1 mg/kg/day, administered orally. The dose may be titrated up to a maximum of 2 mg/kg/day based on succinylacetone levels.

Q2: What are the major side effects of Nitisinone?

A: Common side effects include leukopenia, thrombocytopenia, and ocular issues like corneal keratopathy and conjunctivitis.

Q3: How does Nitisinone work in HT-1?

A: It blocks the enzyme 4-hydroxyphenylpyruvate dioxygenase, preventing the formation of succinylacetone, a toxic metabolite that causes liver and kidney damage in HT-1.

Q4: Are there any dietary restrictions while on Nitisinone for HT-1?

A: Yes, dietary restriction of tyrosine and phenylalanine is crucial to manage HT-1 effectively, along with Nitisinone.

Q5: Can Nitisinone be used during pregnancy?

A: Data is limited, but the potential benefits of Nitisinone for HT-1 management may outweigh the risks in pregnant women. Close monitoring is essential.

Q6: How often should monitoring parameters be checked for patients on Nitisinone?

A: The frequency of monitoring (succinylacetone, liver function tests, etc.) depends on the individual patient’s condition and stability. Regular monitoring is essential, especially during dose adjustments.

Q7: What is the role of Nitisinone in alkaptonuria (AKU)?

A: Nitisinone inhibits the production of homogentisic acid, thus reducing the accumulation of pigments that cause ochronosis and other symptoms of AKU.

Q8: Is there a risk of liver failure if Nitisinone is stopped suddenly in HT-1 patients?

A: Yes, abrupt discontinuation of Nitisinone in HT-1 patients can precipitate liver failure. Dosage should be tapered if discontinuation is necessary.

Q9: Are there any specific drug interactions with Nitisinone that I should be aware of?

A: Drug interaction data is limited. Caution is recommended when administering Nitisinone with drugs metabolized by the liver, and close monitoring is necessary.