PALYNZIQ (pegvaliase-pqpz) injection, for subcutaneous use
Pegvaliase-pqpz is a phenylalanine-metabolizing enzyme that is composed of recombinant phenylalanine ammonia lyase (rAvPAL) conjugated to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG). rAvPAL is manufactured in Escherichia coli bacteria transformed with a plasmid containing the phenylalanine ammonia lyase (PAL) gene derived from Anabaena variabilis.
Pegvaliase-pqpz is a phenylalanine-metabolizing enzyme that is composed of recombinant phenylalanine ammonia lyase (rAvPAL) conjugated to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG). rAvPAL is manufactured in Escherichia coli bacteria transformed with a plasmid containing the phenylalanine ammonia lyase (PAL) gene derived from Anabaena variabilis.
rAvPAL is a homotetrameric protein with a molecular weight of 62 kD per monomer. To produce pegvaliase-pqpz, an average of nine (9) 20 kD PEG molecules are covalently bound (or conjugated) to each monomer of rAvPAL. The total molecular weight of pegvaliase-pqpz (rAvPAL-PEG) is approximately 1000 kD. Palynziq (pegvaliase-pqpz) injection, intended for subcutaneous injection, is a clear to slightly opalescent, colorless to pale yellow, sterile, preservative-free solution and is formulated at pH 6.6 to 7.4.
Palynziq is provided in a single-dose prefilled syringe and is available in three dosage strengths: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL.
CLINICAL PHARMACOLOGY
Mechanism of Action
CLINICAL PHARMACOLOGY
Mechanism of Action
Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.
Pharmacodynamics
Palynziq treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase-pqpz plasma concentrations.
Pharmacokinetics
The pharmacokinetics of pegvaliase-pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase-pqpz. In the first eight weeks of induction and titration treatment, plasma pegvaliase-pqpz concentrations were low to not measurable. At steady state during maintenance treatment with Palynziq 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase-pqpz concentrations were: 11.2 ± 9.0 (0.21 to 29.6) mg/L and 10.4 ± 12.7 (0.18 to 43.1) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with Palynziq at maintenance dosages of 20 mg once daily and 40 mg once daily.
Absorption
The median Tmax was approximately 8 hours. The mean ± SD (range) peak concentration (Cmax) at steady state 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. Distribution The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively.
Elimination
The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 L/h (0.034 to 8.88), respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively.
Metabolism
The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
Excretion
The route of elimination of pegvaliase-pqpz has not been studied in humans.
Initial U.S. Approval: 2018
INDICATIONS AND USAGE
Palynziq is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.
DOSAGE AND ADMINISTRATION
Dosage
Pharmacodynamics
Palynziq treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase-pqpz plasma concentrations.
Pharmacokinetics
The pharmacokinetics of pegvaliase-pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase-pqpz. In the first eight weeks of induction and titration treatment, plasma pegvaliase-pqpz concentrations were low to not measurable. At steady state during maintenance treatment with Palynziq 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase-pqpz concentrations were: 11.2 ± 9.0 (0.21 to 29.6) mg/L and 10.4 ± 12.7 (0.18 to 43.1) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with Palynziq at maintenance dosages of 20 mg once daily and 40 mg once daily.
Absorption
The median Tmax was approximately 8 hours. The mean ± SD (range) peak concentration (Cmax) at steady state 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. Distribution The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively.
Elimination
The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 L/h (0.034 to 8.88), respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively.
Metabolism
The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
Excretion
The route of elimination of pegvaliase-pqpz has not been studied in humans.
Initial U.S. Approval: 2018
INDICATIONS AND USAGE
Palynziq is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.
DOSAGE AND ADMINISTRATION
Dosage
- Obtain baseline blood phenylalanine concentration before initiating treatment.
- The recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks.
- Titrate the dosage in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg subcutaneously once daily. See full prescribing information for the titration regimen.
- Assess patient tolerability, blood phenylalanine concentration, and dietary protein and phenylalanine intake throughout treatment.
- Consider increasing the dosage to a maximum of 40 mg subcutaneously once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks and who have not achieved either a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L.
- Discontinue Palynziq in patients who have not achieved at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily.
- Reduce the dosage and/or modify dietary protein and phenylalanine intake, as needed, to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L.
Blood Phenylalanine Monitoring and Diet
Premedication
DOSAGE FORMS AND STRENGTHS
Injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions, Other than Anaphylaxis
Management should be based on the severity of the reaction, recurrence, and clinical judgement, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.
ADVERSE REACTIONS
Most common adverse reactions (at least 20% in either treatment phase) are: injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
DRUG INTERACTIONS
Effect of Palynziq on Other PEGylated Products: Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment.
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause fetal harm
- Obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established.
- After a maintenance dosage is established, periodically monitor blood phenylalanine concentrations.
- Counsel patients to monitor dietary protein and phenylalanine intake, and adjust as directed by their healthcare provider.
Premedication
- Consider premedication for hypersensitivity reactions. Administration Instructions
- Rotate injection sites. If more than one injection is needed for a single dose, the injection sites should be at least 2 inches away from each other.
DOSAGE FORMS AND STRENGTHS
Injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions, Other than Anaphylaxis
Management should be based on the severity of the reaction, recurrence, and clinical judgement, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.
ADVERSE REACTIONS
Most common adverse reactions (at least 20% in either treatment phase) are: injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
DRUG INTERACTIONS
Effect of Palynziq on Other PEGylated Products: Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment.
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause fetal harm
Reference: Palynziq Package Insert
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