Sodium phenylbutyrate is an adjunctive therapy in the chronic management of urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation. Sodium phenylbutyrate is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life), as well as in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. Neonatal-onset disease was previously almost universally fatal within the first year of life, but, with hemodialysis, the use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate, and sodium phenylacetate), dietary protein restriction, and sometimes essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%. In late-onset deficiency patients, including females heterozygous for OTC deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with sodium phenylbutyrate and dietary protein restriction, the survival rate is 98%. While therapy does impact survival, it does not prevent acute hyperammonemic encephalopathy in the majority of patients. Sodium phenylbutyrate may be required life-long unless orthotopic liver transplantation is elected.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Equally divide the total daily dose and administer with each meal or feeding (i.e., 3 to 6 times/day). If a dose is missed, take the missed dose as soon as possible. There should be at least 3 hours between doses; do not administer double or extra doses.
Oral Solid Formulations
-Administer with a meal.
Other Oral Formulations
Oral powder
-The powder can be administered, after it is prepared, via mouth, gastrostomy tube, or nasogastric tube.
-Review the preparation instructions, as the vehicle used for administration (i.e., food vs. water) affects drug stability.
-Mixing the powder with food (solid or liquid) requires immediate administration. The effect of food on sodium phenylbutyrate has not been determined. Of note, when Buphenyl Powder is added to a liquid, only sodium phenylbutyrate will dissolve, the excipients will not.
-Dissolving the powder in water has been shown to be stable for up to 1 week at room temperature or under refrigeration. Sodium phenylbutyrate is very soluble in water (5 g per 10 mL). When Buphenyl Powder is added to a liquid, only sodium phenylbutyrate will dissolve, the excipients will not.
-Shake the powder container lightly before each use. Measure the dose using the teaspoon or tablespoon that is provided. Each level teaspoon dispenses 3.2 g of powder and 3 g of sodium phenylbutyrate. Each level tablespoon dispenses 9.1 g of powder and 8.6 g of sodium phenylbutyrate.
Oral granules (Olpruva)
-Do not administer via gastrostomy or nasogastric tube.
-Pour the entire contents of the Mix-Aid packet into approximately 4 ounces of water in a cup and stir for at least 30 seconds.
-Pour the entire contents of the Olpruva packet(s) into the suspension and stir for at least 15 seconds.
-Drink the entire suspension within 5 minutes after stirring to minimize dissolution of coating. Pour another 4 ounces of water into the cup and drink to make sure that any Olpruva remaining in the cup is consumed.
-Discard any suspension that is not taken right away after 30 minutes.
Oral granules (Pheburane)
-Administration via gastrostomy or nasogastric tube has not been evaluated.
-Measure the dose using the calibrated dosing spoon that is provided with the product. The dosing spoon is calibrated in grams of sodium phenylbutyrate.
-Swallow the oral granules with a drink (e.g., water, fruit juices, protein-free infant formulas) or sprinkle onto a spoonful of apple sauce or carrot puree; administration with other food has not been studied and is not recommended. Do NOT chew the oral granules or mix into liquids.
-Swallow immediately to minimize dissolution of coating.
During clinical trials, gastrointestinal (GI) adverse events were the most frequently reported adverse reactions in patients treated with sodium phenylbutyrate. Decreased appetite occurred in 4% of all patients. Dysgeusia, as a bad taste or taste aversion, was reported in 3% of patients. Abdominal pain, gastritis, nausea, vomiting, and weight gain were reported at a rate of 2% or less. Constipation, rectal GI bleeding, peptic ulcer disease, and pancreatitis each occurred in one patient.
In female patients, the most common adverse event reported during clinical trials was menstrual dysfunction, defined as amenorrhea or menstrual irregularity, which occurred in at least 3% of treated patients and has been reported in 23% of the menstruating patients.
Headache and depression were reported in 2% or less of patients during clinical trials with sodium phenylbutyrate. Increased exposure to phenylacetate, the metabolically-active compound of sodium phenylbutyrate, may be associated with neurotoxicity in patients with urea cycle disorders. Plasma concentrations of phenylacetate of 3.5 mmol/L or more may produce somnolence, fatigue, and dizziness. If symptoms of vomiting, nausea, headache, somnolence, or confusion are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of sodium phenylbutyrate.
During clinical trials, drug-induced body odor (probably caused by the metabolite, phenylacetate) was reported in 3% of patients and rash was reported in 2% or less.
During clinical trials, arrhythmia exacerbation and edema each occurred in one patient. Syncope was reported in 2% of patients or less.
During clinical trials with sodium phenylbutyrate, anemia (9%), leukopenia (4%), leukocytosis (4%), thrombocytopenia (3%), and thrombocytosis (1%) were reported. Aplastic anemia and ecchymosis each occurred in one patient.
In patients receiving sodium phenylbutyrate during clinical trials, metabolic acidosis (14%), hypoalbuminemia (11%), metabolic alkalosis (7%), hyperchloremia (7%), hypophosphatemia (6%), elevated hepatic enzymes (4% to 6%), decreased total protein (3%), hyperuricemia (2%), hyperphosphatemia (2%), hypernatremia (1%), hypokalemia (1%), and hyperbilirubinemia (1%) were reported. Renal tubular acidosis (RTA) was reported in one patient.
Do not use sodium phenylbutyrate to treat or manage acute hyperammonemia, as this condition is a medical emergency.
In general, these products should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any product component.
The prescribing of sodium phenylbutyrate requires an experienced clinician familiar with the management of patients with urea cycle disorders.
Increased exposure to phenylacetate, the major metabolite of sodium phenylbutyrate, may be associated with neurotoxicity in patients with urea cycle disorders. Consider reducing the dose if neurotoxicity symptoms (e.g., vomiting, nausea, headache, somnolence or confusion) are present in the absence of high ammonia levels or other intercurrent illnesses.
Renal excretion of phenylacetylglutamine (a metabolite of sodium phenylbutyrate) may induce urinary loss of potassium and hypokalemia. Monitor serum potassium during therapy and initiate appropriate treatment when necessary.
Use sodium phenylbutyrate with caution in patients who require sodium restriction, including those with congestive heart failure, cirrhosis, renal disease (nephrosis), severe renal insufficiency, or other clinical states in which there is sodium retention and/or edema. In these patients, evaluate the appropriateness of therapy by calculating the total amount of sodium the patient will receive based on their weight or body surface area. Sodium phenylbutyrate formulations contain approximately 124 to 125 mg of sodium per 1 gram of sodium phenylbutyrate. If a patient develops new-onset edema or worsening edema while on treatment, discontinue sodium phenylbutyrate administration and initate appropriate therapy.
Use sodium phenylbutyrate with caution in patients who have renal impairment. Sodium phenylbutyrate is metabolized in the kidney and phenylacetylglutamine is primarily excreted by the kidney. No studies have been formally conducted in subjects with renal impairment or renal failure. Monitor plasma ammonia levels when starting patients with impaired renal function on sodium phenylbutyrate.
Formal studies of sodium phenylbutyrate have not been conducted in patients with hepatic disease or impairment; use with caution. Start at the lower end of the recommended dosing range and maintain these patients on the lowest dose necessary to control plasma ammonia levels.
Initiate sodium phenylbutyrate carefully in patients who are being treated with corticosteroid therapy. Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.
Avoid use of the Pheburane product (sodium phenylbutyrate granules) in patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency; these granules contain 768 mg of sucrose per gram of sodium phenylbutyrate. This product should also be used with caution in patients with diabetes mellitus. The Olpruva product (sodium phenylbutyrate granules) does not contain sucrose.
Data are insufficient to evaluate for risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes associated with sodium phenylbutyrate use during human pregnancy. Animal studies have not been conducted, however, based on published animal data, phenylacetate may be neurotoxic to the developing brain. Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.
There are no data on the presence of sodium phenylbutyrate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
For use as an adjunctive therapy to standard of care in the chronic management of patients with urea cycle disorders, including ornithine transcarbamoylase (OTC) deficiency, carbamoyl phosphate synthetase (CPS) deficiency, or argininosuccinic acid syntherase (AAS) deficiency:
Oral dosage (tablets):
Adults: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Children and Adolescents weighing 20 kg or more: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Oral dosage (oral powder for oral solution - e.g., Buphenyl, or Pheburane oral pellet granules):
Adults: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Children and Adolescents weighing 20 kg or more: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Infants and Children weighing less than 20 kg: 450 to 600 mg/kg/day PO, given in equally divided doses with each meal or feeding (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Neonates: 450 to 600 mg/kg/day PO, given in equally divided doses with each feeding (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Oral dosage (Olpruva granules for oral suspension):
Adults: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Children and Adolescents weighing 20 kg or more and with a BSA of 1.2 meters-squared or greater: 9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.
Therapeutic Drug Monitoring:
Plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins should be maintained within normal limits, and plasma glutamine should be maintained at concentrations less than 1,000 micromol/L. Serum drug concentrations of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine, should be monitored periodically. Urinalysis, blood chemistry profiles, neurologic exams, and hematologic tests should be performed routinely.
Maximum Dosage Limits:
-Adults
13 g/m2/day (Max: 20 g/day) PO.
-Geriatric
13 g/m2/day (Max: 20 g/day) PO.
-Adolescents
13 g/m2/day (Max: 20 g/day) PO.
-Children
weight 20 kg or more: 13 g/m2/day (Max: 20 g/day) PO.
weight less than 20 kg: 600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.
-Infants
600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.
-Neonates
600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.
Patients with Hepatic Impairment Dosing
For patients with hepatic impairment, initiate therapy with a dosage at the lower end of the recommended dosing range; use the lowest dosage necessary to achieve acceptable ammonia concentrations.
Patients with Renal Impairment Dosing
Monitor ammonia levels closely when starting patients with impaired renal function on sodium phenylbutyrate; specific dosage adjustment guidance is not available.
*non-FDA-approved indication
Albuterol; Budesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Azelastine; Fluticasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Beclomethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Belinostat: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Betamethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide; Formoterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Ciclesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Corticosteroids: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Cortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Deflazacort: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Dexamethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fludrocortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Flunisolide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Salmeterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Vilanterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Formoterol; Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Haloperidol: (Moderate) Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with haloperidol. Haloperidol has been reported to increase plasma ammonia levels (hyperammonemia).
Hydrocortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Methylprednisolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Olopatadine; Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Panobinostat: (Major) Avoid coadministration of sodium phenylbutyrate and panobinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and panobinostat are inhibitors of histone deacetylase (HDAC).
Prednisolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Prednisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Probenecid: (Major) Avoid coadministration of probenecid and sodium phenylbutyrate. Coadministration may increase the risk for potential for neurotoxicity. Probenecid may inhibit renal excretion of the metabolites of sodium phenylbutyrate, including phenylacetate and phenylacetylglutamine.
Probenecid; Colchicine: (Major) Avoid coadministration of probenecid and sodium phenylbutyrate. Coadministration may increase the risk for potential for neurotoxicity. Probenecid may inhibit renal excretion of the metabolites of sodium phenylbutyrate, including phenylacetate and phenylacetylglutamine.
Romidepsin: (Major) Avoid coadministration of sodium phenylbutyrate and romidepsin. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and romidepsin are inhibitors of histone deacetylase (HDAC).
Triamcinolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Trofinetide: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and trofinetide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor.
Valproic Acid, Divalproex Sodium: (Contraindicated) Valproic acid and its analogs are contraindicated in patients with urea cycle disorders, including those being treated with sodium phenylbutyrate. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected urea cycle disorders. Do not administer valproic acid to a patient who is being treated with sodium phenylbutyrate.
Vorinostat: (Major) Avoid coadministration of sodium phenylbutyrate and vorinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and vorinostat are inhibitors of histone deacetylase (HDAC).
Sodium phenylbutyrate is a pro-drug and is rapidly metabolized to phenylacetate. Phenylacetate is a metabolically-active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine, which is excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing two moles of nitrogen). Renal excretion of the glutamine conjugate is an alternate vehicle for waste nitrogen excretion. In patients with urea cycle disorders, sodium phenylbutyrate decreases elevated plasma ammonia and glutamine levels.
Sodium phenylbutyrate is administered orally. The apparent volume of distribution of phenylbutyrate is 7.2 L under fasted conditions. After oral administration, sodium phenylbutyrate is metabolized by beta-oxidation into phenylacetate, which is converted to its coenzyme A ester, phenylacetyl-coenzyme A and further conjugated with glutamine to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. The major sites for metabolism of sodium phenylbutyrate are the liver and kidneys. Phenylacetate is also hydrolyzed by esterases in liver and blood. Approximately 80% to 100% of the administered dose was excreted by the kidneys within 24 hours as the conjugation product. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12 to 0.15 g of phenylacetylglutamine nitrogen are produced. The mean half-life of sodium phenylbutyrate during studies of the oral granules ranged from 0.5 to 0.8 hour.
-Route-Specific Pharmacokinetics
Oral Route
Oral tablets and powder
After oral administration of sodium phenylbutyrate 5 g (tablet) under fasting conditions, measurable plasma concentrations of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. Phenylbutyrate Cmax was 195 mcg/mL at 1 hour after administration of the oral powder and 218 mcg/mL at 1.35 hours after administration of the oral tablets. Phenylacetate Cmax was 45.3 mcg/mL at 3.55 hours after administration of the oral powder and 48.5 mcg/mL at 3.74 hours after administration of the oral tablets. The effect of food on absorption is unknown.
Oral granules
After oral administration of sodium phenylbutyrate 5 g oral granules (Olpruva) under fasting conditions, the mean phenylbutyrate Cmax and AUC were 229 mcg/mL and 510 hour x mcg/mL, respectively. Compared to fasted conditions, the AUC of phenylbutyrate decreased by 39% and Cmax decreased by 50% when administered with a high-fat meal.
After oral administration of sodium phenylbutyrate 3 g oral granules (Pheburane) under fasting conditions, the mean phenylbutyrate Cmax ranged from 146 to 169 mcg/mL at approximately 0.6 hours after administration. The mean phenylbutyrate AUC ranged from 272 to 283 hour x mcg/mL. Compared to fasted conditions, the AUC of phenylbutyrate decreased by 40% to 45% and Cmax decreased by 55% when administered with a high-fat, high-calorie meal. When administered with a normal-fat, normal-calorie, low-protein meal, the AUC of phenylbutyrate decreased by 56% to 63% and Cmax decreased by 43% to 45% compared to fasted conditions.
-Special Populations
Hepatic Impairment
In patients who did not have urea cycle disorders but had impaired hepatic function, the metabolism and excretion of sodium phenylbutyrate were not affected. However, this information was obtained from unvalidated, uncontrolled case studies.
Renal Impairment
Phenylacetylglutamine, a metabolite of sodium phenylbutyrate, is excreted by the kidneys. The pharmacokinetics of sodium phenylbutyrate have not been studied in patients with renal impairment.
Gender Differences
Significant gender differences were found in the pharmacokinetics of phenylbutyrate and phenylacetate, but not for phenylacetylglutamine. The pharmacokinetic parameters (AUC and Cmax), for both plasma phenylbutyrate and phenylacetate were about 30% to 50% greater in females than in males.