Nitisinone

Mechanism of Action

Nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD), blocking the second step in the tyrosine degradation pathway before the deficient FAH enzyme causes HT-1.[17] By inhibiting tyrosine metabolism upstream of FAH, NTBC prevents the accumulation of toxic metabolites in the tyrosine degradation pathway. HPPD is also upstream of homogentisate oxidase, another enzyme in the tyrosine degradation pathway deficient in alkaptonuria.[12][18] Therefore, inhibiting HPPD with nitisinone before the deficient step catalyzed by homogentisate oxidase in alkaptonuria will prevent homogentisic acid accumulation.

Pharmacokinetics

Absorption: The pharmacokinetic characteristics following a single oral administration of nitisinone 30 mg in fasting patients achieved a Cmax of 10.5 μmol/L and a Tmax of 3.5 hrs. A multi-dose regimen of nitisinone 80 mg once daily achieved a Cmax of 120 μmol/L and a Cmax of 4 hrs. Steady-state (SS) was reached within 14 days of dosing in all subjects.

Distribution: In vitro studies have demonstrated that nitisinone exhibits a human plasma protein binding of >95% at 50 μm.

Metabolism: The mean terminal plasma half-life was 54 hours in healthy males receiving single-dose nitisinone. In vitro studies demonstrated that nitisinone is relatively stable in human liver microsomes, with minor metabolism possibly mediated by the CYP3A4 enzyme.

Elimination: The mechanism of NTBC elimination is poorly understood. Studies involving multiple oral doses of 80 mg daily in healthy subjects showed that the mean fraction of the dose excreted as unchanged nitisinone in the urine was 3.0%, suggesting that renal elimination of nitisinone is of minor importance.

Administration

Strength and Dosage Forms

Nitisinone is available as pills, capsules, tablets, and oral suspension. While most forms are available in dosage strengths of 2 mg, 5 mg, 10 mg, and 20 mg, the oral suspension of NTBC is available in 4 mg/mL. The oral capsule form of NTBC is administered 2 hours after meals or at least an hour before a patient plans to eat. Patients with trouble swallowing tablets can be administered NTBC through oral suspension. If patients are intolerant to oral suspension or pills, the pill capsules may be opened, and the contents can be mixed with water immediately before ingesting.

Adult Dosage

NTBC dosage is dependent on body weight (kg). The recommended initial dose should be 0.5 mg/kg twice daily. Patients with persistent detectable levels of succinylacetone in the blood and urine after administration of NTBC should have their doses increased while continuously monitoring SA levels. The maximal approved oral dosage is 2 mg/kg, administered twice daily. 

The dosage of nitisinone is titrated for each patient based on clinical and biochemical responses:

• Clinicians should regularly monitor plasma and urine succinylacetone concentrations, α-fetoprotein levels, and liver function markers.
• If succinylacetone is detectable in blood or urine 4 weeks after starting nitisinone, the nitisinone dosage should be increased to 0.75 mg/kg twice daily. Based on the evaluation of all biochemical parameters, nitisinone may be titrated to a maximum daily dosage of 2 mg/kg.
• If the biochemical response is adequate (ie, succinylacetone is undetectable in blood and urine), titration should only be adjusted according to body weight gain, not plasma tyrosine levels.
• When switching from twice-daily to once-daily dosing during therapy initiation, or if the patient's condition deteriorates, it may be necessary to regularly monitor all available biochemical parameters (ie, urine 5-aminolevulinate (ALA), plasma or urine succinylacetone, and erythrocyte porphobilinogen (PBG)-synthase activity).
• The patient's phenylalanine and tyrosine intake should be restricted to ensure plasma tyrosine levels remain below 500 μmol/L. The dietary tyrosine intake should be assessed in patients with plasma phenylalanine and tyrosine levels above 500 μmol/L. The nitisinone dosage should not be altered to reduce the plasma tyrosine concentration.

The oral suspension is not restricted to mealtimes and may be administered anytime throughout the day. Due to the polyol components included, patients receiving an oral suspension of nitisinone may experience constitutional symptoms such as diarrhea, headaches, or fatigue. The primary elimination mechanism of NTBC is unknown, but it has a half-life of about 54 hours.[19][20][11][21] NTBC inhibits the breakdown of tyrosine, causing an increase in tyrosine concentration in the blood. Thus, it must be administered with dietary restrictions on tyrosine and phenylalanine.

Specific Patient Populations

Hepatic impairment: No dosage adjustments are provided in the manufacturer's labeling for patients with hepatic failure. 

Renal impairment: No dosage adjustments are provided in the manufacturer's labeling for patients with renal failure.

Pregnancy considerations: Documented cases of NTBC administration to pregnant women with HT-1 suggested no harm to the patient and a complete absence of fetal anomalies. Follow-up studies on infants born to HT-1-diagnosed mothers treated with NTBC while pregnant will help clarify the risks of nitisinone use in pregnancy.[22] 

Breastfeeding considerations: The advantages of breastfeeding benefits should be weighed against the mother's requirements for nitisinone and any potential risks to the breastfed infant from either the drug or the mother's medical condition.

Adverse Effects

The most common adverse reactions associated with nitisinone administration are categorized below by system.

Metabolic

• Elevated tyrosine levels 
• Seizures

Hematologic

• Leukopenia
• Granulocytopenia
• Thrombocytopenia

Ocular

• Conjunctivitis
• Eye pain
• Corneal opacities
• Photophobia
• Keratitis
• Cataracts

Dermatological

• Epistaxis
• Exfoliative dermatitis
• Pruritis
• Dry skin
• Maculopapular rash
• Alopecia

An elevated tyrosine level is the most common adverse effect of nitisinone therapy; this is thought to be the best predictor of all other adverse effects, especially the ocular manifestations.[23][24][25] Adverse reactions such as headaches or diarrhea may also occur during nitisinone therapy, especially in patients receiving the oral suspension.[11][21] 

Drug-Drug Interactions

Clinicians should be cautious about administering nitisinone to patients receiving medications metabolized by specific members of the CYP 450 family of enzymes. Nitisinone may cause an increase in the concentration of drugs normally metabolized by CYP2C9 and potentially even decrease drug concentrations of substrates normally metabolized by CYP2E1. Patients taking substrates of CYP2C9 should have their doses modified accordingly while also taking nitisinone to avoid toxicity and exacerbation of adverse effects. Examples of drugs metabolized by CYP2C9 include amitriptyline, diclofenac, fluoxetine, ibuprofen, losartan, naproxen, piroxicam, phenytoin, tolbutamide, torasemide, and warfarin.[26] 

Drug-Food Interactions

Patients must adhere to a diet low in tyrosine and phenylalanine to limit adverse reactions, and tyrosine levels should be closely monitored in patients receiving nitisinone.

Contraindications

There are no known contraindications for nitisinone in patients with hereditary tyrosinemia type 1 (HT-1).[22] Explorational studies aiming to identify potential contraindications with nitisinone treatment are currently underway. One non-randomized study assessed nitisinone’s effect on cytochrome p450 (CYP) enzymes. The investigators observed changes in concentrations of drugs metabolized by specific cytochrome p450 enzymes before and after nitisinone administration. The results indicated that nitisinone was a weak inducer of CYP2E1 and a modest inhibitor of CYP2C9.[27] As discussed previously, clinicians should be cautious when administering nitisinone to patients receiving these medications.

Warning and Precautions

Elevated plasma tyrosine levels: Patients should maintain a concomitant reduction in dietary tyrosine and phenylalanine while undergoing treatment with nitisinone capsules. The nitisinone dosage should not be adjusted to achieve lower plasma tyrosine concentrations. Plasma tyrosine levels should be kept below 500 μmol/L. Insufficient dietary restriction of tyrosine and phenylalanine can result in elevated plasma tyrosine levels, which may contribute to varying degrees of intellectual disability and developmental delays. For patients receiving nitisinone capsules who experience sudden changes in neurological status, a clinical laboratory assessment, including plasma tyrosine levels, should be performed.

Hyperkeratotic plaques: Patients may develop painful hyperkeratotic plaques on the palms and soles.

Leukopenia and thrombocytopenia: Clinicians should monitor for these conditions as part of the treatment regimen.

Monitoring

Patients receiving nitisinone should follow a strict diet low in phenylalanine and tyrosine. Serum levels of phenylalanine and tyrosine should be monitored continuously in patients treated with nitisinone. Phenylalanine should be restricted in the diet because it is a precursor amino acid to tyrosine when it is metabolized by phenylalanine hydroxylase. A deficiency in phenylalanine hydroxylase causes phenylketonuria (PKU).[28] 

NTBC causes an elevation of tyrosine in the blood, which is thought to be the cause of various adverse effects. Laboratory studies have shown that a restrictive diet of phenylalanine alone was ineffective in preventing NTBC-induced tyrosinemia. However, the same studies proved that concurrent restriction of phenylalanine and tyrosine significantly reduces the likelihood of NTBC-induced tyrosinemia. A protein-restricted diet protein also considerably reduced tyrosinemia during NTBC therapy.[29] Rapid neurological disturbances in patients on nitisinone therapy are an indication to obtain tyrosine levels.

A slit-lamp exam should be performed before initiating therapy because of the potential ocular adverse effects associated with nitisinone therapy. Patients experiencing keratopathy or other ocular manifestations should undergo slit-lamp examination. One study showed that corneal keratopathy could occur asymptomatically in patients receiving nitisinone.[30] This finding further highlights the importance of monitoring for ocular side effects in patients with HT-1 and alkaptonuria undergoing NTBC therapy.  

Platelet and white blood cell counts should be monitored due to potential hematological side effects, such as thrombocytopenia and leukopenia. This is especially true of patients presenting with signs and symptoms suggesting a hematological condition. If plasma tyrosine levels are elevated in individuals with HT-1 receiving dietary restrictions and nitisinone, it’s essential to evaluate their dietary intake of tyrosine and phenylalanine.

Toxicity

Toxicity due to nitisinone treatment is primarily encountered in individuals who maintain a regular diet without restricting phenylalanine and tyrosine, which precipitates symptoms of hypertyrosinemia. Tyrosine toxicity can mimic the various hereditary tyrosinemia subtypes, inducing potential neurological symptoms, hyperkeratotic plaques on the palms and soles, intellectual disability, and developmental delay.[6]

Enhancing Healthcare Team Outcomes

Nitisinone is reserved for patients with hereditary tyrosinemia type 1, a life-threatening metabolic disease, or alkaptonuria. Nitisinone therapy is started as soon as an infant is diagnosed. Monitoring for potential adverse effects and possible contraindications is essential to ensure a higher quality of life for patients with HT-1.

Due to the autosomal recessive inheritance pattern of HT-1, a symptomatic diagnosis is usually made in infancy, and nitisinone therapy must be started immediately. Developing a strong patient-physician relationship is essential, as patients with HT-1 require lifelong treatment. Life-long therapy requires all interprofessional healthcare team members to be aware of a patient’s diagnosis and treatment to enhance health outcomes. Treatment with nitisinone and improved healthcare team outcomes significantly increase the life expectancy of patients with HT-1.[31] 

To encourage a healthy relationship among the interprofessional healthcare team, all members should collaborate and coordinate openly and have access to the same patient information. This will set the patient up to receive the most optimal care possible. Each member offers expert input from their respective disciplines, which will enhance the patient treatment strategy, improve health outcomes, and prevent adverse effects associated with nitisinone therapy.