pegloticase

Action and Spectrum

Actions and Spectrum: 

pegloticase is a medication used to treat chronic refractory gout, a type of arthritis caused by accumulation of uric acid crystals in joints. It is a pegylated recombinant uricase enzyme. 

Action: pegloticase converts uric acid into allantoin, a soluble and easily excreted compound. Uricase is an enzyme naturally found in the body that breaks down uric acid. However, humans do not produce a functional form of uricase, accumulating uric acid crystals in the joints and other tissues. 

When pegloticase is administered, it enzymatically converts uric acid into allantoin, which is more soluble in water and can be easily eliminated through the kidneys. By decreasing uric acid levels in the body, pegloticase helps dissolve existing uric acid crystals, alleviate symptoms of gout, and prevent further crystal formation. 

Spectrum: pegloticase is specifically indicated for treating chronic refractory gout in adult patients who have not responded adequately to conventional therapies or are unable to tolerate those therapies.  

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Nausea (12%) 

Infusion reactions (26%) 

Urticaria (10.6%) 

Gout flares (77%) 

1-10% 

Chest discomfort (9.5%) 

Nasopharyngitis (7%) 

Pruritus (9.5%) 

Anaphylaxis (5%) 

Chest pain (9.5%) 

Erythema (9.5%) 

Black Box Warning

Black Box Warning: 

The black box warning for pegloticase relates to the risk of anaphylaxis, a severe and potentially life-threatening allergic reaction. Anaphylaxis can occur following the administration of pegloticase. 

The black box warning states that anaphylaxis has been observed during and after pegloticase infusion. Symptoms of anaphylaxis may include difficulty breathing, wheezing, swelling of the face or throat, hives, itching, dizziness, rapid heartbeat, and chest discomfort. Anaphylaxis requires immediate medical attention and treatment. 

Due to the risk of anaphylaxis, pegloticase should only be administered in a guidance of healthcare setting by healthcare professionals experienced in managing anaphylaxis and equipped to respond to an allergic reaction.  

Additionally, patients who have experienced anaphylaxis or other severe allergic reactions to pegloticase should not receive further treatment with the medication. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

pegloticase has several contraindications, which are conditions or circumstances in which medication use is not recommended due to the potential risks involved. The contraindications of pegloticase include: 

• Anaphylaxis or severe allergic reactions: Patients who have experienced anaphylaxis or severe allergic reactions to pegloticase or any of its drug components should not receive further treatment with the medication. 
• G6PD deficiency: pegloticase can cause hemolysis (breakdown of red blood cells) in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is a type of genetic disorder that affects red blood cells’ ability to handle oxidative stress. Due to the risk of severe hemolysis, pegloticase is contraindicated in patients with known G6PD deficiency. 
• Use with other uricase agents: Concurrent use of pegloticase with other uricase agents, such as rasburicase, is contraindicated. Combining these medications can enhance the risk of anaphylaxis. 
• Pregnancy: pegloticase should not be used during pregnancy condition unless the potential benefits outweigh the potential risks to the fetus.  
• Breastfeeding: It is unknown whether pegloticase is excreted in human milk.  

Caution 

Specific cautions should be taken into consideration when using pegloticase. Cautions indicate situations where the medication can still be used but require careful monitoring or adjustments. The cautions associated with pegloticase include: 

• Risk of anaphylaxis: Although anaphylaxis is listed as a contraindication, it is also worth mentioning as a caution due to its potential severity. Anaphylaxis can occur during or after pegloticase infusion, even in patients who have not previously experienced an allergic reaction. Physician should be prepared to manage anaphylaxis, and patients should be monitored during and after each infusion. 
• Gout flares: pegloticase treatment can initially trigger gout flares due to the dissolution of uric acid crystals. Patients should be generally informed about the possibility of experiencing gout flares and provided with appropriate prophylactic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine, to prevent or manage these flares during the early stages of pegloticase therapy. 
• Cardiovascular disease: pegloticase has not been studied extensively in patients with a prior history of CVD (cardiovascular disease). Caution should be exercised when administering pegloticase to patients with a high cardiovascular risk, like those with an earlier history of heart disease or a high risk of cardiovascular events. 
• Hepatic impairment: pegloticase is primarily cleared by the liver, and its pharmacokinetics may be altered in patients with hepatic impairment. Monitoring of liver function tests (LFT) is generally recommended in patients with pre-existing liver disease or impaired hepatic function. 
• Renal impairment: pegloticase has yet to be studied extensively in patients with renal impairment. It is recommended to exercise caution and closely monitor patients with pre-existing renal impairment or reduced renal function. 
• Immunogenicity: The development of antibodies against pegloticase has been observed in some patients, which may reduce the medication’s effectiveness. Monitoring the development of antibodies and evaluating the impact on treatment response is essential. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk is Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

pegloticase is a medication that belongs to the class of drugs known as uric acid-lowering agents. Its pharmacology involves the enzymatic conversion of uric acid into allantoin, leading to decreased uric acid levels in the body. Here are the critical aspects of the pharmacology of pegloticase: 

pegloticase is a pegylated recombinant uricase enzyme. It works by catalyzing the enzymatic oxidation of uric acid into allantoin. Uric acid is a byproduct substance of purine metabolism and is typically excreted from the body. However, humans lack the enzyme uricase that breaks down uric acid into the more soluble allantoin. This can leads to the accumulation of uric acid in the body, leading to gout and other related conditions. 

pegloticase, a recombinant uricase enzyme, provides the missing enzymatic activity in individuals with gout. By converting uric acid into allantoin, pegloticase increases the solubility of uric acid, facilitating its excretion through the kidneys. This helps reduce uric acid levels in the body and dissolve uric acid crystals deposited in joints and other tissues. 

Pharmacodynamics: 

Mechanism of action: The action of pegloticase involves its enzymatic activity as a uricase enzyme. Here’s a detailed explanation of how pegloticase works: 

• Uric Acid Metabolism: Uric acid is a byproduct of purine metabolism in the body. Under normal conditions, uric acid is further broken down into a more soluble compound called allantoin by the enzyme uricase. The kidneys efficiently excrete allantoin. 
• Deficiency of Uricase in Humans: Unlike some other mammals, including mammals other than humans and certain primates, humans lack the functional uricase enzyme. As a result, uric acid is not efficiently converted into allantoin, leading to its accumulation in the body. 
• Role of Uric Acid in Gout: Elevated uric acid levels in the blood can leads to the formation, deposition of uric acid crystals in joints and other tissues. This can cause inflammation, pain, and other symptoms associated with gout. 
• Enzymatic Conversion by pegloticase: pegloticase is a recombinant uricase enzyme that mimics the activity of the natural uricase enzyme. When administered pegloticase, it enzymatically converts uric acid into allantoin, just like the endogenous uricase would do. This enzymatic conversion occurs extracellularly, meaning outside the cells. 
• Reduction of Uric Acid Levels: By converting uric acid into allantoin, pegloticase helps lower uric acid levels in the blood. This reduction in uric acid levels can lead to the dissolution of existing uric acid crystals in joints and other tissues, reducing inflammation and relieving symptoms associated with gout. 

Pharmacokinetics: 

Absorption 

pegloticase is administered intravenously, and as a result, its absorption step is bypassed since it is delivered directly into the bloodstream. 

Distribution 

After administration, pegloticase is distributed throughout the body via systemic circulation. The specific distribution characteristics, such as volume of distribution, tissue penetration, or binding to plasma proteins, are not well-documented in the available literature. 

Metabolism 

pegloticase is a recombinant enzyme designed to mimic the activity of the uricase enzyme found naturally in the body. It undergoes metabolism via enzymatic degradation, primarily in the liver. However, pegloticase’s specific metabolic pathways or metabolites have yet to be extensively characterized. 

Elimination and Excretion 

pegloticase and its metabolites are eliminated from the body primarily via renal excretion. It is important to note that pegloticase is a relatively sizeable protein-based molecule, and its elimination kinetics may differ from small-molecule drugs. The exact details of the excretion process, including clearance rates or renal handling, have yet to be extensively described in the available literature. 

Adminstartion

Administration: 

Intravenous administration 

The pegloticase is administered via intravenous infusion directly into the bloodstream through a vein. Here is a general overview of the administration process: 

• Preparation: The healthcare professional prepares the pegloticase infusion by reconstituting the lyophilized powder with the provided diluent. This process involves mixing the powder and diluent according to the manufacturer’s instructions. The resulting solution is clear and colorless. 
• Intravenous line setup: A sterile intravenous line is established using a suitable intravenous catheter or needle, typically in the arm or hand. 
• Pre-medication (optional): Depending on the patient’s needs and the healthcare provider’s recommendation, pre-medication may be administered before pegloticase infusion. Pre-medication can help reduce the risk of infusion reactions, including anaphylaxis. Standard pre-medication options include antihistamines, corticosteroids, and NSAIDs. 
• Infusion process: The pegloticase solution is administered slowly over a specified time. The infusion duration and rate may vary depending on the specific treatment protocol the healthcare provider prescribes. Typically, the initial infusion is given over at least 2 hours. 
• Monitoring: During the infusion, the patient is monitored for any signs of an allergic reactions or infusion-related adverse events, including anaphylaxis. Vital signs such as BP, heart rate, and respiratory rate are regularly checked. Healthcare professionals are prepared to respond promptly to any adverse reactions. 
• Post-infusion monitoring: Following the completion of the infusion, patients are usually monitored for some time, typically 30-60 minutes, to ensure stability and evaluate for any delayed adverse reactions. 
• Subsequent infusions: pegloticase is typically administered every two weeks, with subsequent infusions following a similar process as described above. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: pegloticase 

Pronounced: [ peg-LOE-ti-kase ] 

Why do we use pegloticase? 

The pegloticase is primarily used to treat chronic refractory gout in adult patients. Chronic refractory gout refers to a form of gout that has not responded adequately to conventional therapies or for patients who cannot tolerate those therapies. Here are the primary uses of pegloticase: 

• Chronic Refractory Gout: pegloticase is indicated for managing chronic refractory gout in adult patients. It is specifically used for those without sufficient control of gout symptoms and reduction in uric acid levels with other medications such as allopurinol or febuxostat. pegloticase is considered when gout symptoms are severe and there is a high uric acid crystal deposition burden. 
• Uric Acid Reduction: pegloticase converts uric acid into allantoin, a more soluble and easily excreted compound. By decreasing uric acid levels in the body, pegloticase helps dissolve existing uric acid crystals in the joints and other tissues. This can alleviate gout symptoms, including joint pain, inflammation, and swelling. 

It’s important to note that pegloticase is not intended to treat acute gout attacks. Instead, it is used for long-term management of chronic refractory gout. pegloticase is typically used when other treatment options have been exhausted or are ineffective in controlling gout symptoms and reducing uric acid levels. A healthcare professional makes the decision to use pegloticase based on the individual patient’s condition, severity of symptoms, and response to other treatments.