Glycerol phenylbutyrate

Glycerol phenylbutyrate
Clinical data
Trade namesRavicti
Other namesGlyceryl phenylbutyrate; GPB; GT4P; HPN-100; HPN100
AHFS/Drugs.comMicromedex Detailed Consumer Information
License data
Routes of
administration		Oral
Drug classHistone deacetylase inhibitor; Ammonia scavenger
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolites• Phenylbutyric acid
• Phenylacetic acid
• Phenylacetylglutamine
Elimination half-lifeUnknown (very rapid)[4][5]
Identifiers
  • 1,2,3-propanetriyl tris(4-phenylbutanoate)
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.228.552
Chemical and physical data
FormulaC33H38O6
Molar mass530.661 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)CCCC(=O)OCC(COC(=O)CCCC2=CC=CC=C2)OC(=O)CCCC3=CC=CC=C3
  • InChI=1S/C33H38O6/c34-31(22-10-19-27-13-4-1-5-14-27)37-25-30(39-33(36)24-12-21-29-17-8-3-9-18-29)26-38-32(35)23-11-20-28-15-6-2-7-16-28/h1-9,13-18,30H,10-12,19-26H2
  • Key:ZSDBFLMJVAGKOU-UHFFFAOYSA-N

Glycerol phenylbutyrate (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name), sold under the brand name Ravicti, is a nitrogen-binding agent medication used for chronic management of certain urea cycle disorders. The medication reduces the harmful buildup of ammonia in the body.[6] It functions as a prodrug of phenylbutyric acid, which conjugates with glutamine to form phenylacetylglutamine, facilitating ammonia excretion via the kidneys

It was developed by Hyperion Therapeutics based on the existing medication sodium phenylbutyrate, and received FDA approval in February 2013.[7][8]

Medical uses

Glycerol phenylbutyrate is indicated for chronic management of people with inborn urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.[2][9]

Pharmacology

Pharmacodynamics

Glycerol phenylbutyrate is an ammonia scavenger.[10][4] It is a prodrug of phenylbutyric acid (phenylbutyrate), which acts by binding to nitrogen and conjugating with glutamine (which contains nitrogen) via acetylation to form phenylacetylglutamine (PAGN).[10][4] In addition to its ammonia-scavenging activity, phenylbutyric acid is a histone deacetylase (HDAC) inhibitor.[11][12][13][14]

Pharmacokinetics

The elimination half-life of glycerol phenylbutyrate is unknown or not described.[4][5] It is very rapidly hydrolyzed into phenylbutyric acid (PBA; phenylbutyrate) in vitro and unchanged glycerol phenylbutyrate is undetectable in blood in vivo.[5] One study, in people with cirrhosis, found that the half-lives of glycerol phenylbutyrate's metabolites were 1.9 hours (range 0.8–7.4 hours) for phenylbutyric acid, 1.0–1.8 hours for phenylacetic acid (PAA), and 1.9–16.9 hours for phenylacetylglutamine (PAGN).[15]

Chemistry

Analogues

Analogues of glycerol phenylbutyrate include phenylbutyric acid (phenylbutyrate), tributyrin (glycerol tributyrate), and glyceryl-tris-3-hydroxybutyrate (3GHB), among others.

History

Glycerol phenylbutyrate was first approved for medical use in the United States in 2013.[16]

Society and culture

Economics

Hyperion has been criticized for setting a high price for the drug. The price was set at US$250,000–290,000. In 2014, the drug generated $30.8 million in net sales, far behind the older and less expensive Buphenyl ($113.6 million in sales).[17]

Patents

While GPB is the subject of several patents related to its synthesis, formulation, and therapeutic monitoring, the core patent covering its composition and use in treating UCDs is US 5,968,979. Subsequent patents build on this foundation, focusing on manufacturing improvements, dosing methods, and related applications. Below is a summary of key issued US patents explicitly addressing GPB's use in UCDs, based on patent database records. Note that patents often cover broader nitrogen retention disorders, including UCDs as a primary indication.

Issued US patents

Patent NumberTitleIssue dateAssignee/InventorSummary of Relevance to UCD Treatment
US 5,968,979 Glycerol ester derivatives October 19, 1999 Children's Medical Center Corp. (Boston, MA); Saul W. Brusilow, Marshall L. Summar Foundational patent for GPB (glyceryl tri-(4-phenylbutyrate) or HPN-100) as a nitrogen-scavenging agent. Claims methods for treating UCDs by administering GPB to reduce hyperammonemia, with dosages of 5–10 g/m²/day. Enabled FDA approval in 2013.[18]"Ravicti Label" (PDF). U.S. Food and Drug Administration. Retrieved 14 October 2025.
US 9,914,692 Procedure for the preparation of 4-phenyl butyrate and uses thereof March 13, 2018 Horizon Therapeutics Ireland DAC; Bruce A. Bloom, Mitchell L. Chan Describes synthesis of 4-phenylbutyric acid (GPB precursor) via oxidation of 4-phenyl-1-butanol. Claims use of GPB in treating UCDs and hepatic encephalopathy, emphasizing >99% purity for ammonia control.[19]
US 10,045,959 Methods of therapeutic monitoring of nitrogen scavenging drugs August 14, 2018 Horizon Therapeutics USA, Inc.; Jeffrey L. Gelfand, Bruce A. Bloom Covers methods to monitor and adjust GPB dosing in UCD patients using fasting ammonia levels. Includes dose titration algorithms to maintain ammonia <0.5 mmol/L, improving long-term management.[20]
US 9,999,608 Methods of therapeutic monitoring of nitrogen scavenging drugs June 19, 2018 Horizon Therapeutics USA, Inc.; Jeffrey L. Gelfand, Bruce A. Bloom Continuation of US 10,045,959, focusing on predictive modeling of ammonia exposure to prevent hyperammonemic crises in UCD patients, with clinical data from pediatric and adult cohorts.[21]

Additional Notes Patent Expiry: US 5,968,979 expired in 2018, potentially allowing generic GPB formulations by late 2025. Later patents (e.g., US 9,914,692) extend protection for synthesis methods until ~2035–2038."Ravicti Patent Expirations". Deep knowledge on small-molecule drugs and the global patents covering them. DrugPatentWatch. 6 August 2026. Retrieved 14 October 2025. Related Patents: International patents (e.g., WO 2015/063659) and pending US applications (e.g., US 2021/0114996 for RNA-modulating therapies) mention GPB but are not issued US patents.[22] Clinical Context: These patents supported trials showing GPB reduces ammonia by ~30% compared to sodium phenylbutyrate, leading to FDA approval for patients ≥2 months.

Additional Notes

Scope and Expiry: US 5,968,979 expired in 2018, aligning with the entry of generic GPB formulations expected by late 2025. Later patents (e.g., US 9,914,692) extend protection for manufacturing processes, potentially affecting generics until around 2035-2038. Related but Non-US or Pending: International equivalents (e.g., WO 2015/063659 for GPB synthesis) and US applications (e.g., US 2021/0114996 for RNA-modulating therapies in UCDs mentioning GPB) exist but are not issued US patents. Clinical Context: These patents supported pivotal trials (e.g., phase 3 studies showing GPB reduces ammonia by 30% vs. sodium phenylbutyrate) leading to FDA approval for all ages ≥2 months.

Research

Glycerol phenylbutyrate was developed by Ucyclyd Pharma, Horizon Pharma, and other organizations.[9] In addition to inborn urea cycle disorders, it is under development for the treatment of cystic fibrosis.[9] As of February 2026, the drug is in 1/2 clinical trials for this indication.[9] Glycerol phenylbutyrate was also under development for the treatment of hepatic encephalopathy, but development for this use was discontinued.[9]

References

  1. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada. 14 March 2017. Retrieved 7 April 2024.
  2. 1 2 "Ravicti- glycerol phenylbutyrate liquid". DailyMed. 13 September 2021. Archived from the original on 3 May 2023. Retrieved 4 July 2023.
  3. ↑ "Ravicti EPAR". European Medicines Agency (EMA). 10 June 2010. Retrieved 20 February 2025.
  4. 1 2 3 4 "Glycerol phenylbutyrate: Uses, Interactions, Mechanism of Action". DrugBank. Retrieved 5 August 2026. Glycerol phenylbutyrate is a prodrug - the major metabolite, phenylacetate (PAA) is the molecule that binds to nitrogen. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted by the kidneys. PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.
  5. 1 2 3 "FDA2013" (PDF). www.accessdata.fda.gov.
  6. ↑ "FDA approves new drug for the chronic management of some urea cycle disorders" (Press release). U.S. Food and Drug Administration (FDA). 1 February 2013. Archived from the original on 7 March 2013. Retrieved 1 April 2013.
  7. ↑ "Drug Approval Package: Ravicti (glycerol phenylbutyrate) Oral Liquid NDA #203284". U.S. Food and Drug Administration (FDA). 28 March 2013. Archived from the original on 1 August 2016. Retrieved 20 February 2025.
  8. ↑ Herder M (April 2016). "Orphan drug incentives in the pharmacogenomic context: policy responses in the USA and Canada". Journal of Law and the Biosciences. 3 (1): 158–166. doi:10.1093/jlb/lsv060. PMC 5033429. PMID 27774236.
  9. 1 2 3 4 5 "Glycerol phenylbutyrate". AdisInsight. 11 February 2026. Retrieved 5 August 2026.
  10. 1 2 Rahimi RS, Rockey DC (August 2015). "Novel Ammonia-Lowering Agents for Hepatic Encephalopathy". Clinics in Liver Disease. 19 (3): 539–549. doi:10.1016/j.cld.2015.04.008. PMID 26195207.
  11. ↑ Nott A, Fass DM, Haggarty SJ, Tsai LH (2013). "HDAC Inhibitors as Novel Therapeutics in Aging and Alzheimer's Disease". Epigenetic Regulation in the Nervous System. Elsevier. pp. 225–248. doi:10.1016/b978-0-12-391494-1.00008-2. ISBN 978-0-12-391494-1. Retrieved 31 July 2026.
  12. ↑ Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, et al. (October 2010). "Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin". ACS Medicinal Chemistry Letters. 2 (1): 39–42. doi:10.1021/ml1001954. PMC 3161516. PMID 21874153. Table 1. In Vitro Potency of Carboxylic and Hydroxamic Acid HDAC Inhibitorsa [...]
  13. ↑ Gore SD, Carducci MA (December 2000). "Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors". Expert Opinion on Investigational Drugs. 9 (12): 2923–2934. doi:10.1517/13543784.9.12.2923. PMID 11093362.
  14. ↑ Kusaczuk M, Bartoszewicz M, Cechowska-Pasko M (2015). "Phenylbutyric Acid: simple structure - multiple effects". Current Pharmaceutical Design. 21 (16): 2147–2166. doi:10.2174/1381612821666150105160059. PMID 25557635.
  15. ↑ McGuire BM, Zupanets IA, Lowe ME, Xiao X, Syplyviy VA, Monteleone J, et al. (June 2010). "Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis". Hepatology. 51 (6). Baltimore, Md.: 2077–2085. doi:10.1002/hep.23589. PMC 3733097. PMID 20512995. The mean plasma half-life of PBA after GPB administration was 1.9 (± 1.7) hours and ranged from 0.8 to 7.4 hours. The plasma half-lives for PAA and PAGN after GPB administration ranged from 1.0 to 1.8 hours and 1.9 to 16.9 hours, respectively.
  16. ↑ Levin J (1 February 2013). "FDA NEWS RELEASE: FDA approves new drug for the chronic management of some urea cycle disorders". Fierce Biotech. Retrieved 5 August 2026.
  17. ↑ Staff GE (30 March 2015). "Horizon Pharma to Acquire Hyperion Therapeutics for $1.1B". GEN - Genetic Engineering and Biotechnology News. GEN - Genetic Engineering and Biotechnology News. Archived from the original on 26 August 2017. Retrieved 18 February 2018.
  18. ↑ US 5968979, Brusilow SW, Marshall L, "Glycerol ester derivatives", published 19 October 1999, issued 19 October 1999, assigned to Children's Medical Center Corp.
  19. ↑ US 9914692, Bloom BA, Mitchell L, "Procedure for the preparation of 4-phenyl butyrate and uses thereof", published 13 March 2018, issued 13 March 2018, assigned to Horizon Therapeutics Ireland DAC and Horizon Therapeutics US Holding LLC
  20. ↑ US 10045959, Gelfand JL, Bruce A, "Methods of therapeutic monitoring of nitrogen scavenging drugs", published 14 August 2018, issued 14 August 2018, assigned to Horizon Therapeutics USA, Inc. and Horizon Therapeutics US Holding LLC
  21. ↑ US 9999608, Gelfand JL, Bruce A, "Methods of therapeutic monitoring of nitrogen scavenging drugs", published 19 June 2018, issued 19 June 2018, assigned to Horizon Therapeutics USA, Inc. and Horizon Therapeutics US Holding LLC
  22. ↑ WO 2015063659, Jadhav SP, Mahajan DP, Nehate SP, Godbole HM, Singh GP, "Process for preparation of glycerol phenylbutyrate", published 7 May 2015, issued 7 May 2015, assigned to Lupin Ltd
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