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  • CLASSES

    Urea Cycle Disorder Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Nitrogen-binding agent
    Used for chronic management of urea cycle disorders (UCD)
    Contraindicated in infants younger than 2 months

    COMMON BRAND NAMES

    RAVICTI

    HOW SUPPLIED

    RAVICTI Oral Sol: 1mL, 1.1g

    DOSAGE & INDICATIONS

    For the chronic management of hyperammonemia in patients with urea cycle disorders.
    NOTE: Glycerol phenylbutyrate is designated as an orphan drug for the maintenance treatment of patients with urea cycle enzyme deficiencies.
    Oral dosage
    Adults switching from sodium phenylbutyrate

    For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into 3 equal doses and round each dose up to the nearest 0.5 mL. Max daily dose: 17.5 mL (19 g).

    Adults (phenylbutyrate naive)

    4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into 3 equal doses, each rounded up to the nearest 0.5 mL (Max: 17.5 mL/day [19 g/day]). Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.

    Children and Adolescents 2 to 17 years switching from sodium phenylbutyrate

    For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into 3 equal doses and round each dose up to the nearest 0.5 mL. Max daily dose: 17.5 mL (19 g).

    Children and Adolescents 2 to 17 years (phenylbutyrate naive)

    4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into 3 equal doses, each rounded up to the nearest 0.5 mL (Max: 17.5 mL/day [19 g/day]). Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.

    Infants and Children 2 months to 1 year switching from sodium phenylbutyrate

    For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into at least 3 equal doses and round each dose up to the nearest 0.1 mL. Max daily dose: 17.5 mL (19 g).

    Infants and Children 2 months to 1 year (phenylbutyrate-naive)

    4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into at least 3 equal doses, each rounded up to the nearest 0.1 mL (Max: 17.5 mL/day [19 g/day]). Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.

    MAXIMUM DOSAGE

    Adults

    17.5 mL/day (19 g/day) PO.

    Geriatric

    17.5 mL/day (19 g/day) PO.

    Adolescents

    17.5 mL/day (19 g/day) PO.

    Children

    17.5 mL/day (19 g/day) PO.

    Infants

    2 to 11 months: 17.5 mL/day (19 g/day) PO.
    younger than 2 months: Use is contraindicated.

    Neonates

    Use is contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    For patients with moderate to severe hepatic impairment, initiate therapy with a dosage at the lower end of the recommended dosing range (4.5 mL/m2/day); use the lowest dosage necessary to achieve acceptable ammonia concentrations.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. Initial dosage adjustments are not required; however, ammonia concentrations should be closely monitored and dosages adjusted accordingly.

    ADMINISTRATION

    Oral Administration
    Oral Liquid Formulations

    All patients who can swallow should be administered glycerol phenylbutyrate orally, even those with a nasogastric or gastrostomy tube. For patients who cannot swallow, follow recommendations for nasogastric or gastrostomy tube administration.
     
    Oral Administration
    Administer with food or formula.
    Measure the dose with an oral syringe or dosing cup and administer directly into the mouth.
     
    Nasogastric tube or Gastrostomy tube Administration
    Withdraw prescribed dose from the bottle.
    Place the tip of the syringe into the tip of the gastrostomy/nasogastric tube to administer dose.
    After administration, flush once with 10 mL of water or formula and allow the flush to drain. If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.
    For patients who require a volume of less than 1 mL per dose via nasogastric or gastrotomy tube, the delivered dose may be less than expected due to adherence of glycerol phenylbutyrate to the plastic tubing. Therefore, monitor these patients closely using ammonia concentrations after initiation of glycerol phenylbutyrate dosing or dosage adjustments.

    STORAGE

    RAVICTI:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Glycerol phenylbutyrate is contraindicated in patients with known phenylbutyrate hypersensitivity.

    Infants, neonates

    Glycerol phenylbutyrate is contraindicated in neonates and infants younger than 2 months of age due to their immature pancreatic exocrine function, which could impair hydrolysis of glycerol phenylbutyrate and lead to impaired absorption of phenylbutyrate and hyperammonemia.

    Fat malabsorption, pancreatic insufficiency

    Use glycerol phenylbutyrate cautiously and monitor ammonia concentrations closely in patients with pancreatic insufficiency or fat malabsorption syndromes. Pancreatic enzymes in the small intestine are responsible for separating phenylbutyrate, the active moiety, from the glycerol backbone. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal conditions resulting in fat malabsorption may impair or prohibit the digestion of glycerol phenylbutyrate, which may result in reduced phenylbutyrate absorption and ultimately less control of plasma ammonia concentrations.

    Hepatic disease

    Use glycerol phenylbutyrate cautiously in patients with hepatic disease and initiate therapy at the low end of the dosage range in patients with moderate to severe hepatic impairment. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted in the urine. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion ability, which may result in increased PAA concentrations. PAA has been associated with neurotoxicity. Signs of neurotoxicity may include somnolence, fatigue, lightheadedness, headache, dysgeusia, hearing impairment, disorientation, impaired memory, seizures, and exacerbation of preexisting neuropathy. If neurotoxicity symptoms develop in the absence of high ammonia levels or other intercurrent illnesses, reduce the dosage of glycerol phenylbutyrate.

    Renal disease, renal impairment

    Safety and efficacy of glycerol phenylbutyrate have not been established in patients with renal impairment. Monitor ammonia concentrations closely in patients with impaired renal function. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN); PAGN is then excreted in the urine. The effects of renal disease on the conversion of PAA to PAGN or the excretion of PAGN have not been defined.

    Requires an experienced clinician

    The prescribing of glycerol phenylbutyrate requires an experienced clinician familiar with the management of patients with urea cycle disorders.

    Pregnancy

    The limited data available in pregnant women are insufficient to determine a drug-associated risk of major birth defects and miscarriage in humans. No effects on embryo-fetal development were observed in rabbits or rats when doses approximately 2 to 3 times an adult dose of glycerol phenylbutyrate 6.87 mL/m2/day were administered during the period of organogenesis; however, maternal toxicity was observed at doses approximately 3 times an adult dose of 6.87 mL/m2/day. Maternal toxicity, reduced fetal weights, and variations in skeletal development were observed when pregnant rats were given doses greater than or equal to 5.7 times a dose of 6.87 mL/m2/day. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to glycerol phenylbutyrate during pregnancy. For more information regarding the registry program and to report pregnancy exposure, visit www.ucdregistry.com or call 1-855-823-2595.

    Breast-feeding

    It is not known whether glycerol phenylbutyrate is excreted in human milk, affects milk production, or has an adverse effect on nursing infants. However, because of the potential for serious adverse effects, including neurotoxicity and tumorigenicity in nursing infants, breast-feeding is not recommended with maternal use of glycerol phenylbutyrate.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 10.0
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    memory impairment / Delayed / Incidence not known

    Mild

    flatulence / Early / 14.0-14.0
    dyspepsia / Early / 5.0-5.0
    headache / Early / 10.0
    dizziness / Early / 10.0
    fatigue / Early / 7.0
    abdominal pain / Early / 7.0
    diarrhea / Early / 10.0
    nausea / Early / 2.0
    vomiting / Early / 7.0
    anorexia / Delayed / 7.0
    rash (unspecified) / Early / 10.0
    fever / Early / 10.0
    rhinorrhea / Early / 10.0
    nasal congestion / Early / 10.0
    cough / Delayed / 10.0
    drowsiness / Early / Incidence not known
    tremor / Early / Incidence not known
    dysgeusia / Early / Incidence not known

    DRUG INTERACTIONS

    Alfentanil: (Moderate) Concomitant use of glycerol phenylbutyrate and alfentanil may result in decreased exposure of alfentanil. Alfentanil is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of alfentanil during coadministration.
    Azelastine; Fluticasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Beclomethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concomitant use of glycerol phenylbutyrate and ergotamine may result in decreased exposure of ergotamine. Ergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ergotamine during coadministration.
    Betamethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Budesonide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Budesonide; Formoterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Caffeine; Ergotamine: (Moderate) Concomitant use of glycerol phenylbutyrate and ergotamine may result in decreased exposure of ergotamine. Ergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ergotamine during coadministration.
    Carbamazepine: (Moderate) Concomitant use of glycerol phenylbutyrate and carbamazepine may result in decreased exposure of carbamazepine. Carbamazepine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of carbamazepine during coadministration.
    Ciclesonide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Corticosteroids: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Corticotropin, ACTH: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Cortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Cyclosporine: (Moderate) Concomitant use of glycerol phenylbutyrate and cyclosporine may result in decreased exposure of cyclosporine. Cyclosporine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of cyclosporine during coadministration.
    Deflazacort: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Dexamethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Dextromethorphan; Quinidine: (Moderate) Concomitant use of glycerol phenylbutyrate and quinidine may result in decreased exposure of quinidine. Quinidine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of quinidine during coadministration.
    Dihydroergotamine: (Moderate) Concomitant use of glycerol phenylbutyrate and dihydroergotamine may result in decreased exposure of dihydroergotamine. Dihydroergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of dihydroergotamine during coadministration.
    Ergotamine: (Moderate) Concomitant use of glycerol phenylbutyrate and ergotamine may result in decreased exposure of ergotamine. Ergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ergotamine during coadministration.
    Ethosuximide: (Moderate) Concomitant use of glycerol phenylbutyrate and ethosuximide may result in decreased exposure of ethosuximide. Ethosuximide is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ethosuximide during coadministration.
    Fentanyl: (Moderate) Concomitant use of glycerol phenylbutyrate and fentanyl may result in decreased exposure of fentanyl. Fentanyl is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of fentanyl during coadministration.
    Fludrocortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Flunisolide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Fluticasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Fluticasone; Salmeterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Fluticasone; Vilanterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Formoterol; Mometasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Haloperidol: (Moderate) Haloperidol may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of haloperidol and glycerol phenylbutyrate is necessary.
    Hydrocortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Methylprednisolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Midazolam: (Moderate) Concomitant use of glycerol phenylbutyrate and midazolam may result in decreased exposure of midazolam. Monitor for decreased efficacy of midazolam during coadministration. Midazolam is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. In a drug interaction study in healthy subjects, coadministration with glycerol phenylbutyrate reduced the mean Cmax and AUC of midazolam by 25% and 32%, respectively, compared to administration of midazolam alone. Additionally, the mean Cmax and AUC for 1-hydroxy midazolam were 28% and 52% higher, respectively, compared to administration of midazolam alone.
    Mometasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Pimozide: (Moderate) Concomitant use of glycerol phenylbutyrate and pimozide may result in decreased exposure of pimozide. Pimozide is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of pimozide during coadministration.
    Prednisolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Prednisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Probenecid: (Moderate) Probenecid may inhibit renal excretion of glycerol phenylbutyrate metabolites, including phenylacetate (PAA) and phenylacetylglutamine (PAGN). PAA has been associated with neurotoxicity. If probenecid must be used in combination with glycerol phenylbutyrate, monitor the patient closely for signs and symptoms of neurotoxicity. In addition, because probenecid alters PAGN excretion, use caution when interpreting urinary PAGN concentrations for the purpose of dosage adjustments.
    Quinidine: (Moderate) Concomitant use of glycerol phenylbutyrate and quinidine may result in decreased exposure of quinidine. Quinidine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of quinidine during coadministration.
    Sirolimus: (Moderate) Concomitant use of glycerol phenylbutyrate and sirolimus may result in decreased exposure of sirolimus. Sirolimus is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of sirolimus during coadministration.
    Tacrolimus: (Moderate) Concomitant use of glycerol phenylbutyrate and tacrolimus may result in decreased exposure of tacrolimus. Tacrolimus is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of tacrolimus during coadministration.
    Theophylline, Aminophylline: (Moderate) Concomitant use of glycerol phenylbutyrate and theophylline may result in decreased exposure of theophylline. Theophylline is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of theophylline during coadministration.
    Triamcinolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
    Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of valproic acid and glycerol phenylbutyrate is necessary.
    Warfarin: (Moderate) Concomitant use of glycerol phenylbutyrate and warfarin may result in decreased exposure of warfarin. Warfarin is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of warfarin during coadministration.

    PREGNANCY AND LACTATION

    Pregnancy

    The limited data available in pregnant women are insufficient to determine a drug-associated risk of major birth defects and miscarriage in humans. No effects on embryo-fetal development were observed in rabbits or rats when doses approximately 2 to 3 times an adult dose of glycerol phenylbutyrate 6.87 mL/m2/day were administered during the period of organogenesis; however, maternal toxicity was observed at doses approximately 3 times an adult dose of 6.87 mL/m2/day. Maternal toxicity, reduced fetal weights, and variations in skeletal development were observed when pregnant rats were given doses greater than or equal to 5.7 times a dose of 6.87 mL/m2/day. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to glycerol phenylbutyrate during pregnancy. For more information regarding the registry program and to report pregnancy exposure, visit www.ucdregistry.com or call 1-855-823-2595.

    It is not known whether glycerol phenylbutyrate is excreted in human milk, affects milk production, or has an adverse effect on nursing infants. However, because of the potential for serious adverse effects, including neurotoxicity and tumorigenicity in nursing infants, breast-feeding is not recommended with maternal use of glycerol phenylbutyrate.

    MECHANISM OF ACTION

    Glycerol phenylbutyrate is a triglyceride that contains 3 molecules of phenylbutyrate. It serves as an alternative vehicle for waste nitrogen excretion, which helps to reduce blood ammonia and glutamine concentrations in patients with certain urea cycle disorders. Patients with high blood ammonia and glutamine concentrations are at particular risk for encephalopathies and neurotoxicity.
     
    The urea cycle is responsible for maintaining low blood concentrations of ammonia and glutamine produced by protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to convert ammonia into nitrogenous waste (i.e., urea) that can be excreted from the body. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or transporters. Ammonia in the blood is converted to glutamine. Phenylacetate, the major metabolite of glycerol phenylbutyrate, conjugates with glutamine in the liver and kidneys to form glutamine phenylacetate, which is then acetylated to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. Similar to urea, two moles of nitrogen are removed per mole of phenylacetylglutamine.

    PHARMACOKINETICS

    Glycerol phenylbutyrate is administered orally. Pancreatic lipases hydrolyze glycerol phenylbutyrate and release phenylbutyrate (PBA) from the glycerol backbone. PBA is converted by beta-oxidation to phenylacetate (PAA), which is then conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN). In healthy subjects, exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. PAGN is eliminated in the urine. In vitro pharmacokinetic studies found protein binding to be 81% to 98% for PBA (over 1 to 250 mcg/mL); 37% to 66% for PAA (over 5 to 500 mcg/mL); and 7% to 12% for PAGN (no concentration effects noted). During a premarketing pharmacokinetic study, the mean percentage of administered PBA excreted as PAGN was approximately 69% in adult patients with a urea cycle disorder (UCD) and 66% in pediatric UCD patients. PAA and PBA were also detected in the urine and accounted for less than 1% of the administered dose.
     
    Possibly affected cytochrome P450 isoenzymes: CYP2C9, CYP2D6, and CYP3A4/5
    During in vitro studies, phenylbutyrate (PBA), at a concentration of 800 mcg/mL, caused more than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5. In addition, inhibition of CYP1A2, CYP2C8, CYP2C19, and CYP2D6 by phenylacetate (PAA) at a concentration of 2,800 mcg/mL was observed in vitro. However, in healthy subjects who received glycerol phenylbutyrate 6 mL PO 3 times daily for 3 days, the mean PBA and PPA Cmax were 100 mcg/mL and 65 mcg/mL, respectively. The clinical implications of the in vitro data are not known.

    Oral Route

    Glycerol phenylbutyrate is a prodrug. When orally ingested, pancreatic lipases in the gastrointestinal tract release phenylbutyrate (PBA) from the glycerol backbone. In healthy fasting adults who received a single oral dose of glycerol phenylbutyrate 2.9 mL/m2, peak PBA, PAA, and PAGN plasma concentrations occurred at 2 hours, 4 hours, and 4 hours, respectively. In adult UCD patients who received multiple doses, maximum plasma concentrations at steady state of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day.