Continuing Education Activity

The FDA first approved nitisinone in 2002 for managing and treating hereditary tyrosinemia type 1 (HT-1). HT-1 is an autosomal recessive disease caused by a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway. This activity reviews the indications, action, and contraindications for nitisinone as a valuable agent in treating HT-1 and its off-label use in managing alkaptonuria. This activity highlights the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, monitoring) of nitisinone therapy, pertinent for members of the interprofessional healthcare team in managing hereditary tyrosinemia type 1 and related metabolic disorders.

Objectives:

• Summarize the mechanism of action of nitisinone.
• Review the conditions where nitisinone use is indicated.
• Identify common and rare adverse effects of nitisinone and potential contraindications.
• Explain the importance of interprofessional team collaboration and communication to improve health outcomes for patients receiving treatment with nitisinone.

Indications

Nitisinone, or 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC), was first approved by the U.S (United States) Food and Drug Administration (FDA) for the treatment of hereditary tyrosinemia type 1 (HT-1), in 2002. It was first discovered as a triketone molecule part of herbicidal weed killers.[1][2] 

HT-1 is an autosomal recessive disease caused by a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway.[3] Among the general population, HT-1 has a prevalence of about 1/100,000 newborn infants. Diagnosis is made via molecular studies and enzyme studies, with symptoms of HT-1 arising early in life. Death occurs within 24 months (about two years) if patients are not treated as soon as possible.[4]

HT-1 complications arise from the accumulation of tyrosine and intermediate products fumarylacetoacetate (FAA) and maleylacetoacetate (MAA). FAA deposition in renal tubules and hepatocytes precipitates end-organ damage. Intermediate by-products, FAA and MAA, are further broken down into toxic metabolites, succinylacetoacetate (SAA) and succinylacetone (SA), in patients with HT-1.[5][6] 

Subsequent elevations of SAA and SA further exacerbate liver and kidney toxicity. Rickets, cognitive impairments, jaundice, vomiting, persistent irritability, and renal tubular dysfunction are among the most common symptoms caused by HT-1.[5] Hepatocellular Carcinoma (HCC) is a late complication of hereditary tyrosinemia type 1 and is a significant cause of death.[7] HT-1 patients are more likely to progress to hepatocellular carcinoma (HCC), especially when they are not provided with proper neonatal screening or access to NTBC medication. Recurring checkup appointments should be scheduled to monitor for HCC continuously.[7]  

SA can also lead to a decrease in heme synthesis due to the inhibition of delta-aminolevulinic acid dehydratase (ALAD), the enzyme necessary to catalyze the conversion of aminolevulinic acid to porphobilinogen. This causes an accumulation of aminolevulinic acid (ALA). This same step in heme synthesis is inhibited by lead. Therefore, it would not be unusual for a patient with HT-1 to have porphyria-type symptoms similar to lead poisoning.[8][9]

Succinylacetone is a reliable screening marker analyzed in patient blood, helpful in the diagnosis and screening of HT-1. Succinylacetone is also the preferred marker when monitoring disease treatment's effect.[10] Methionine elevation in HT-1 patients is a marker for hepatocellular injury.[11][4] Before the utilization of NTBC, the definitive treatment for HT-1 was liver transplantation. This therapy method is still used for HT-1 patients who are refractory to NTBC treatment.[11] 

Non-FDA-approved indications for NTBC use include the management of alkaptonuria.[12] Alkaptonuria is an autosomal recessive disorder in which homogentisic acid (HGA), a pigmenting toxic metabolite, accumulates in cartilage, sclera, and connective tissues (ochronosis).[13] 

Recent studies suggest NTBC therapy may be more beneficial in treating patients with alkaptonuria than in those with HT-1. A more recent study investigated nitisinone's effectiveness in treating alkaptonuria by comparing a 2 mg dose of nitisinone to a 10 mg dose of nitisinone. The results indicated that nitisinone 10 mg slows the progressive disease course of alkaptonuria and leads to a more significant decrease in urine and serum HGA levels. The study also highlighted the increased likelihood of developing adverse effects with a higher dose of nitisinone compared to the lower amount and the benefit of concurrent adherence to a low-protein diet.[14]

More recently, nitisinone has been explored for its potential use in improving regional hypopigmentation in patients with albinism. Multiple subtypes of oculocutaneous albinism (OCA) exist, and mutations in the tyrosinase gene cause this inherited disorder. A deficiency in tyrosinase leads to a decrease in melanin synthesis. This lack of melanin gives patients with OCA the typical presentation of a lack of pigmentation of the skin, eyes, and hair follicles.[15] 

One group of researchers tested the efficacy of nitisinone therapy in treating five patients with OCA-1B. Their results concluded that nitisinone might prove beneficial in increasing the pigmentation of the skin and hair in patients with OCA-1B.[16] 

Mechanism of Action

Nitisinone blocks the second step in the tyrosine degradation pathway before the deficient FAH enzyme causes HT-1 by inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD).[17] Thus, through inhibiting tyrosine metabolism upstream of FAH, NTBC prevents the accumulation of toxic metabolites of 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. 

Administration

Nitisinone is approved for oral use via pill capsules or oral suspension and should be administered as soon as the diagnosis of HT-1 is confirmed. 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 oral capsule form of NTBC is administered either two hours after meals or at least an hour before a patient plans on eating. Patients with trouble swallowing tablets can be given NTBC administered 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 use.

Usage of oral suspension is not limited to mealtimes and can be taken at any time throughout the day. Nitisinone is currently approved in dosage strengths of 2 mg, 5 mg, 10 mg, and 20 mg. The oral suspension of NTBC is approved at a dose of 4 mg/ml. Patients receiving an oral suspension of nitisinone could have constitutional symptoms such as diarrhea, headaches, or fatigue due to the polyol components included. The excretion of NTBC is unknown, and 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 of tyrosine and phenylalanine. 

Adverse Effects

The most common adverse reactions associated with nitisinone use include 

Adverse Metabolic Reactions

• Elevated levels of tyrosine 
• Seizures 

Adverse Blood Reactions

• Leukopenia  
• Granulocytopenia 
• Thrombocytopenia  

Adverse Ocular Reactions

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

Adverse Dermatological Reactions

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

Elevation in tyrosine levels is the most common adverse effect of nitisinone drug use. It has been proposed that elevated levels of tyrosine, because of nitisinone therapy, is the most predicted cause of these adverse effects, especially the ocular manifestations.[22][23][24]

Adverse reactions such as headaches or diarrhea may also occur with nitisinone use, especially in those receiving therapy by an oral suspension.[11][21] 

Patients must adhere to a diet low in tyrosine and phenylalanine to limit the eruptions of adverse reactions, and tyrosine levels are actively monitored while taking nitisinone. 

Contraindications

There are no known contraindications for using nitisinone in treating hereditary tyrosinemia type 1. Previous cases of NTBC use in pregnant patients with HT-1 showed 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.[25]

Explorational experiments to identify potential contraindications with nitisinone treatment are being conducted. A non-randomized study was previously shown to assess nitisinone’s effect on cytochrome p450 (CYP) enzymes. The investigators tested 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.[26] 

Nitisinone may be contraindicated with the concurrent use of drugs metabolized by these 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.[27]  

Monitoring

Nitisinone should be administered with a diet strictly 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 is the cause of phenylketonuria (PKU).[28] 

NTBC causes an elevation of tyrosine in the blood, which is thought to be the cause of many 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 NTBC-induced tyrosinemia. A diet utterly restrictive of protein, composed of amino acids, also considerably reduced tyrosinemia after NTBC therapy.[29] Rapid neurological disturbances in patients on nitisinone therapy call for an evaluation of tyrosine levels. 

Because of the potential ocular adverse effects of nitisinone treatment, a slit-lamp exam should be done before beginning treatment. Patients experiencing keratopathy or other ocular manifestations should be subjected to slit-lamp examination. A previous study showed that corneal keratopathy could occur asymptomatically in patients treated with nitisinone.[30] This finding further highlights the importance of monitoring for ocular side effects of HT-1 and alkaptonuria patients on NTBC.  

Due to potential hematological side effects such as thrombocytopenia and leukopenia, platelet and white blood cell counts should be monitored. This is especially true of patients presenting with signs and symptoms of hematological pathology.  

Toxicity

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

Enhancing Healthcare Team Outcomes

The prescription of nitisinone is reserved for patients with the life-threatening metabolic disease, hereditary tyrosinemia type 1, and can also be used in treating alkaptonuria. Nitisinone therapy is started as soon as a diagnosis is made in an infant. Monitoring nitisinone uses for potential adverse effects and possible contraindications are essential to ensuring 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. Due to this, developing a strong and trusting patient-physician relationship is essential, as HT-1 patients will be treated for life. Life-long therapy requires all interprofessional healthcare team members to be aware of an HT-1 patient’s diagnosis and treatment to enhance health outcomes. Treatment with nitisinone and improved healthcare team outcomes have significantly increased the life expectancy of patients with HT-1.[31] 

The interprofessional healthcare team members include all clinicians (MDs and DOs), physician assistants, nurse practitioners, the nursing staff, and pharmacists. To encourage a healthy relationship among the interprofessional healthcare team, all members should collaborate and coordinate openly, and each should 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 undesired adverse effects from nitisinone use. [Level 5]