pegvaliase

Action and Spectrum

Actions and Spectrum 

Action:

Drug acts as a phenylalanine-metabolizing enzyme that converts phenylalanine into a different compound called trans-cinnamic acid. This enzymatic action helps reduce the levels of phenylalanine in the body of individuals with phenylketonuria. By breaking down phenylalanine, drug aims to maintain phenylalanine levels within an acceptable range, thereby preventing the toxic buildup of phenylalanine that can cause neurological and cognitive impairments associated with phenylketonuria. 

Spectrum:

Drug is specifically designed for the treatment of Phenylketonuria. It targets individuals with Phenylketonuria who have high phenylalanine levels and are unable to effectively metabolize phenylalanine due to a deficiency in the enzyme phenylalanine hydroxylase (PAH). PAH deficiency is the underlying cause of PKU, and drug provides an alternative mechanism for phenylalanine metabolism in these individuals. 

Drug Interaction

Adverse Reaction

Frequency defined  

>10% (Induction/titration) 

Pruritus (20%) 

Headache (35%) 

Complement factor C4 below LLN (62%) 

Hypersensitivity reactions (53%) 

C-reactive protein (CRP) above ULN (64%) 

Arthralgia (74%) 

Injection site reactions (88%) 

Complement factor C3 below LLN (68%)  

>10% (Maintenance) 

Hypersensitivity reactions (61%) 

Headache (50%) 

Nausea (26%) 

Abdominal pain (25%) 

Vomiting (26%)  

CPK above ULN (43%) 

CRP above ULN (68%) 

Complement factor C4 below LLN (48%) 

Hypophenylalaninemia on a single measurement (61%) 

Injection site reactions (72%) 

Generalized skin reaction lasting at least 14 days (37%) 

Arthralgia (61%) 

Complement factor C3 below LLN (84%) 

1-10% 

Induction/titration 

Nasal congestion (4%) 

Anxiety (5%) 

Diarrhea (9%) 

Alopecia (5%) 

Cough (9%) 

Black Box Warning

Black Box Warning:  

Anaphylaxis 

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity: Individuals who have experienced a severe allergic reaction (anaphylaxis) or hypersensitivity to pegvaliase or any of its components should not use the medication. 

Active or uncontrolled infection: pegvaliase can suppress the immune system, so it is contraindicated in individuals with active or uncontrolled infections. 

Poorly controlled hypertension: pegvaliase may increase blood pressure in some individuals. If a patient’s blood pressure is not well-controlled and remains elevated despite treatment, the use of pegvaliase may be contraindicated. 

History of blood clotting disorders: Drug may increase the risk of blood clot formation. Individuals with a history of blood clotting disorders or those who are at an increased risk of developing blood clots should exercise caution when considering pegvaliase. 

Pregnancy and breast-feeding: The safety of pegvaliase during pregnancy and breastfeeding has not been established. Therefore, its use is generally contraindicated in these situations.

Hepatic impairment: Drug is primarily metabolized in the liver. Individuals with severe hepatic impairment may have a reduced ability to metabolize the medication, which could increase the risk of adverse effects. The use of pegvaliase should be carefully considered in such cases. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: AU TGA Pregnancy Category: D
US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

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:  

pegvaliase is a medication used in the treatment of phenylketonuria, a rare genetic disorder characterized by the inability to metabolize an amino acid called phenylalanine. 

Pharmacodynamics:  

pegvaliase is an enzyme substitution therapy that utilizes a modified form of the enzyme phenylalanine ammonia-lyase (PAL). PAL is normally produced by bacteria and plants but is not present in humans. Bacteria and plants normally produce PAL but is not present in humans. This modification extends the half-life of the enzyme and reduces its immunogenicity.   

Pharmacokinetics: 

Absorption 

The drug is administered via subcutaneous injection, slowly absorbed into the bloodstream. The absorption rate and bioavailability of drug have yet to be extensively studied, but it is expected to exhibit sustained release characteristics due to its pegylated form. 

Distribution 

Following absorption, drug is expected to distribute throughout the body, reaching the tissues and organs where it can act on phenylalanine. The specific distribution characteristics, such as volume of distribution, need to be well-documented. 

Metabolism 

Drug is a recombinant enzyme derived from Pegylated phenylalanine ammonia lyase (PAL), which is a bacterial enzyme. In the body, drug works by converting phenylalanine into ammonia and trans-cinnamic acid, thereby reducing its levels in individuals with Phenylketonuria. drug is not expected to undergo significant metabolism itself. 

Excretion and Elimination 

The Drug is primarily eliminated from the body through renal excretion. However, the exact elimination kinetics and half-life of drug have not been extensively studied. It is worth noting that individual patient factors, such as renal function, may affect the elimination of pegvaliase. 

Adminstartion

Administration:  

Subcutaneous Injection: The drug is administered via subcutaneous injection, which is injected under the skin. The injections are usually given once daily, preferably in the thigh or abdomen. The healthcare provider will determine the exact dosage and injection site based on the patient’s needs. 

Dose Titration: The initial doses of drug are typically low and gradually increased over several weeks to minimize the risk of side effects. This process, known as dose titration, allows the patient’s body to adjust to the medication and helps manage any potential adverse reactions. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: pegvaliase 

Why do we use pegvaliase?  

Phenylketonuria (PKU) Treatment: Drug is a long-term treatment option for adults with PKU who have inadequate control of their blood Phe levels through dietary restrictions alone. PKU patients have a deficiency in the enzyme phenylalanine hydroxylase (PAH), leading to Phe’s buildup in the blood.

Drug is a modified form of the enzyme phenylalanine ammonia lyase (PAL), which can convert Phe into other substances that can be eliminated from the body. By replacing the deficient enzyme, the drug helps to lower blood Phe levels.