Molecular mass: 318.414 g/mol PubChem compound: 86278362
Pegvaliase is a PEGylated recombinant phenylalanine ammonia lyase enzyme that converts phenylalanine to ammonia and trans-cinnamic acid that are primarily eliminated by liver metabolism.
Pegvaliase is a PEGylated recombinant phenylalanine ammonia lyase (rAvPAL), derived from the cyanobacterium Anabaena variabilis expressed in Escherichia coli. The purpose of the PEGylation of rAvPAL is to reduce immune recognition of the rAvPAL bacterial protein and increase the half-life.
The pharmacokinetics of pegvaliase exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Immune response affects clearance and time to reach steady state. The immune response stabilises over 6 to 9 months of total treatment.
Following a single subcutaneous dose (0.01, 0.03 or 0.1 mg/kg), pegvaliase is absorbed slowly with a median tmax of 3.5 to 4 days (individual range of 2.5 to 7 days). The bioavailability is not affected by the different injection sites on the body. The absolute bioavailability in humans is unknown.
Mean (SD) for apparent volume of distribution (Vz/F) at steady state following 20 mg and 40 mg doses was 26.4 L (64.8 L) and 22.2 L (19.7 L) respectively.
Following cellular uptake, the metabolism of phenylalanine ammonia lyase (PAL) is expected to occur via catabolic pathways and be degraded into small peptides and amino acids; the PEG molecule is metabolically stable and expected to be separated from PAL protein and primarily eliminated by renal filtration.
Pegvaliase is primarily cleared by immune-mediated mechanisms following repeat dosing. In clinical trials, anti-PAL, anti-PEG and anti-pegvaliase have been identified as IgG and IgM mainly. Relatively low titres of IgE has also been observed. In maintenance phase of the treatment, steady state is expected 4 to 24 weeks after maintenance dose started. A mean (SD) half-life at 20 mg and 40 mg were 47.3 hours (41.6 hours) and 60.2 hours (44.6 hours), respectively. Individual values for half-life range from 14 to 132 hours. The PEG molecule is expected to be primarily eliminated by renal filtration.
During dose escalation from 20 mg/day to 40 mg/day and 40 mg/day to 60 mg/day, a greater dose proportional increase in exposure was observed.
Analysis of pegvaliase concentration data from clinical trials indicated that body weight, gender and age did not have a notable effect on pegvaliase pharmacokinetics. No clinical trials have been conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of pegvaliase.
A PK/PD analysis using the Phase III data demonstrated an inverse pegvaliase exposure-phenylalanine response relationship, which could be influenced by dietary phenylalanine intake. At lower plasma pegvaliase Ctrough concentrations <10 000 ng/ml, patients with higher dietary phenylalanine intake tend to have higher blood phenylalanine levels compared to patients with the same Ctrough concentration and lower dietary phenylalanine intake, suggesting saturation of the enzyme (i.e. rAvPAL). At high pegvaliase Ctrough concentrations ≥10 000 ng/ml, the majority of the blood phenylalanine levels (97%) are ≤30 micromol/l, even when dietary phenylalanine intake is high. Therefore, a reduction in pegvaliase dose should be considered in patients experiencing hypophenylalaninaemia despite appropriate levels of protein intake.
Dose-dependent reductions in body weight gain attributed to decreased plasma phenylalanine levels to below normal levels in normal animals (monkeys, rats and rabbits) was observed in single and repeat dose toxicology studies as well as developmental and reproductive toxicity studies with pegvaliase. Decreased plasma phenylalanine and reduced body weight gain was reversible after cessation of treatment.
In cynomolgus monkeys, the incidence and severity of arterial inflammation was dose dependent and observed in a wide range of organs and tissues at clinically relevant exposures in the 4- and 39-week repeat-dose toxicology studies. The arterial inflammation observed in these studies involved small arteries and arterioles in a wide range of organs and tissues and in subcutaneous injection sites. Arteritis was attributed to the immune-mediated response associated with chronic administration of foreign protein to the animals. The vascular inflammation observed in these studies was reversible upon cessation of treatment.
In rats, dose dependent vacuolation attributed to pegvaliase treatment was observed at clinically relevant exposures in the 4- and 26-week repeat-dose toxicity studies in rats in multiple organs and tissues, but not in cynomolgus monkeys. No vacuolation was observed in the brain. Vacuoles in all tissues, with the exception of the kidney, resolved or were diminished by the end of the recovery period, suggesting partialsee reversibility. The vacuolation observed in these studies was not associated with any organ related toxicities as determined by clinical chemistry/urinalysis and histopathological analysis. The clinical significance of these findings and functional consequences are unknown.
Adverse reproductive and developmental effects of pegvaliase in rats and rabbits were dose dependent and included reduced implantation rate, smaller litter size, lower foetal weights, and increased foetal alterations. Additional findings in rabbits included increased abortions, foetal malformations and embryo/foetal lethality. These findings occurred in the presence of maternal toxicity (decreased body weights, decreased ovarian weights, and decreased food consumption) and were associated with markedly decreased maternal blood phenylalanine below normal levels in non-PKU animals. The contribution of maternal phenylalanine depletion to the incidence of embryo-foetal developmental effects was not evaluated.
In the peri/postnatal study, pegvaliase decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously. The effects in offspring were associated with maternal toxicity.
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with pegvaliase. Based on its mechanism of action, pegvaliase is not expected to be tumorigenic.
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