Pegvaliase API Manufacturers

General Description:

Pegvaliase, identified by CAS number 1585984-95-7, is a notable compound with significant therapeutic applications. Pegvaliase is a recombinant phenylalanine ammonia lyase (PAL) enzyme derived from _Anabaena variabilis_ that converts phenylalanine to ammonia and _trans_-cinnamic acid . Both the U.S. Food and Drug Administration and European Medicines Agency approved pegvaliase-pqpz in May 2018 for the treatment of adult patients with phenylketonuria (PKU). Phenylketonuria is a rare autosomal recessive disorder that is characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH) and affects about 1 in 10,000 to 15,000 people in the United States . PAH deficiency and inability to break down an amino acid phenylalanine (Phe) leads to elevated blood phenylalanine concentrations and accumulation of neurotoxic Phe in the brain, causing chronic intellectual, neurodevelopmental and psychiatric disabilities if untreated . Individuals with PKU also need to be under a strictly restricted diet as Phe is present in foods and products with high-intensity sweeteners . The primary goal of lifelong treatment of PKU, as recommended by the American College of Medical Genetics and Genomics (ACMG) guidelines, is to maintain blood Phe concentration in the range of 120 µmol/L to 3690 µmol/L . Pegvaliase-pqpz, or PEGylated pegvaliase, is used as a novel enzyme substitution therapy and is marketed as Palynziq for subcutaneous injection. Pegvaliase-pqpz is a homotetrameric protein composed of recombinant phenylalanine ammonia lyase (rAvPAL) conjugated to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG). It is advantageous over currently available management therapies for PKU, such as , that are ineffective to many patients due to long-term adherence issues or inadequate Phe-lowering effects . The presence of a PEG moiety in pegvaliase-pqpz allows a reduced immune response and improved pharmacodynamic stability .

Indications:

This drug is primarily indicated for: Pegvaliase is indicated for the management of phenylketonuria (PKU) in adult patients who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pegvaliase undergoes metabolic processing primarily in: It is expected that pegvaliase undergoes the catabolic pathway to be degraded into small peptides and amino acids . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pegvaliase are crucial for its therapeutic efficacy: At steady state during maintenance treatment with pegvaliase 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) peak plasma concentration (Cmax) was 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively . The time to reach Cmax (Tmax) was approximately 8 hours . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pegvaliase is an important consideration for its dosing schedule: Following once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, the mean ± SD (range) half-life at steady state was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pegvaliase exhibits a strong affinity for binding with plasma proteins: No protein binding has been reported. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pegvaliase from the body primarily occurs through: Human elimination pathway of pegvaliase has not been studied. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pegvaliase is distributed throughout the body with a volume of distribution of: The mean ± SD (range) apparent volume of distribution at steady state was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L after once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, respectively . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pegvaliase is a critical factor in determining its safe and effective dosage: At steady state following once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, the mean ± SD (range) apparent clearance was 0.39 ± 0.87 L/h and 1.25 ± 2.46 L/h, respectively . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pegvaliase exerts its therapeutic effects through: In a phase 3 clinical trial of adult patients with phenylketonuria and blood phenylalanine concentrations greater than 600 µmol/L on existing management therapies, subcutaneous administration of pegvaliase resulted in significantly reduced blood phenylalanine concentrations in most patients compared to their pre-treatment baseline levels within 24 months in addition to improved neuropsychiatric symptoms . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pegvaliase functions by: Pegvaliase is a phenylalanine ammonia lyase (PAL) enzyme that temporarily restores the levels of deficient enzyme and reduces blood phenylalanine concentrations by converting phenylalanine to ammonia and _trans_-cinnamic acid . Formed conversion products are metabolized in the liver and later excreted in the urine . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Pegvaliase is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Amino Acids, Peptides, and Proteins, Ammonia-Lyases, Carbon-Nitrogen Lyases, Enzymes, Enzymes and Coenzymes, Lyases, Pegylated agents, Phenylalanine Metabolizing Enzyme, Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Pegvaliase include:

• Molecular Weight: 1000000.0