Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC code: A16AX03.

Mechanism of action and pharmacodynamic effects
Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate.
Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion.

Clinical efficacy and safety
Based on studies of phenylacetylglutamine excretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are produced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine levels in patients with urea cycle disorders. It is important that the diagnosis is made early and treatment is initiated immediately to improve the survival and the clinical outcome.

In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically with dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of the patients who were tested had an IQ in the average to low average/borderline mentally retarded range. Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic deterioration may continue in some patients.

PHEBURANE may be required life-long unless orthotropic liver transplantation is elected.

Paediatric population
Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth (but within the first month of life) increased to almost 80 % with most deaths occurring during an episode of acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental retardation.

In patients diagnosed during gestation and treated prior to any episode of hyperammonaemic encephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated cognitive impairment or other neurologic deficits.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with glutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by esterases in liver and blood.

Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting normal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea cycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to 20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been studied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or phenylacetate.

Absorption
Phenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylbutyrate were detected 15 minutes after dosing. The mean time to peak concentration was 1 hour and the mean peak concentration 195 μg/ml. The elimination half-life was estimated to be 0.8 hours. The effect of food on absorption is unknown.

Distribution
The volume of distribution of phenylbutyrate is 0.2 l/kg.

Biotransformation
After a single dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylacetate and phenylacetylglutamine were detected 30 and 60 minutes respectively after dosing. The mean time to peak concentration was 3.55 and 3.23 hours, respectively, and the mean peak concentration was 45.3 and 62.8 μg/ml, respectively. The elimination half-life was estimated to be 1.3 and 2.4 hours, respectively.

Studies with high intravenous doses of phenylacetate showed non-linear pharmacokinetics characterised by saturable metabolism to phenylacetylglutamine.
Repeated dosing with phenylacetate showed evidence of an induction of clearance.

In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses of phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be detected after overnight fasting. In patients with impaired hepatic function the conversion of phenylacetate to phenylacetylglutamine may be relatively slower.
Three cirrhotic patients (out of 6) who received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed sustained plasma levels of phenylacetate on the third day that were five times higher than those achieved after the first dose.

In normal volunteers gender differences were found in the pharmacokinetic parameters of phenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not phenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent differences in volume of distribution.

Excretion
Approximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the conjugated product, phenylacetylglutamine.