Glycerol phenylbutyrate
Glycerol phenylbutyrate was approved by the U.S. Food and Drug Administration (FDA) on Feb 1, 2013, then approved by European Medicine Agency (EMA) on Nov 27, 2015. It was developed and marketed as Ravicti® by Hyperion Therapeutics in USA and by Horizon Therapeutics in EU.
Glycerol phenylbutyrate contains an agent that binds the nitrogen. It works by removing the toxic ammonia accumulated in the blood and the brain of the urea cycle disorder (UCD)-affected patients. The drug also keeps the ammonia in the body at safe levels throughout the day and night. It is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥ two years of age with urea cycle disorders (UCDs) that can not be managed by dietary protein restriction and/or amino acid supplementation alone.
Ravicti® is available as liquid for oral use, containing 1.1 g/mL of Glycerol phenylbutyrate. The recommended daily dose is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) taking with food.
Update Date：2016-03-14
- Drug Name：
- Glycerol phenylbutyrate
- Research Code：
- PRO-13050530
- Trade Name：
- Ravicti®
- MOA：
- Nitrogen-binding agent
- Indication：
- Urea cycle disorders (UCDs)
- Status：
- Approved
- Company：
- Hyperion Therapeutics (Originator)
- Sales：
-
$95.4 Million (Y2014);
$31.2 Million (Y2013); - ATC Code：
- A16AX09
Update Date：2016-03-03
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-02-01 | Marketing approval | Ravicti | Urea cycle disorders (UCDs) | Liquid | 1.1 g/mL of glycerol phenylbutyrate | Hyperion Therapeutics | Orphan |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2015-11-27 | First approval | Ravicti | Urea cycle disorders (UCDs) | Liquid | 1.1 g/mL of glycerol phenylbutyrate | Horizon | Orphan |
Update Date：2015-08-27
|
Molecular Weight | 530.67 | ||||||||||||
| Formula | C33H38O6 | |||||||||||||
| CAS No. | 611168-24-2 (Glycerol phenylbutyrate); | |||||||||||||
| Chemical Name | 1,3-bis[(4-phenylbutanoyl)oxy]propan-2-yl 4-phenylbutanoate | |||||||||||||
| Glycerol phenylbutyrate （Free Acid/Base）Parameters： | ||||||||||||||
|
||||||||||||||
| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2016-02-02
Update Date：2016-06-07
Mechanism of Action
Glycerol phenylbutyrate is a triglyceride containing three molecules of PBA linked to a glycerol backbone.
Glycerol phenylbutyrate was metabolized to PBA and then PAA, which is subsequently conjugated with glutamine to form PAGN in the liver and kidneys.
PAGN was excreted in urine, thereby acting as a substitute for urea by mediating nitrogen excretion.
Update Date：2016-06-07
Absorption of Glycerol Phenylbutyrate
Glycerol phenylbutyrate was a pro-drug of PBA. PBA was released from the glycerol backbone in the gastrointestinal tract by lipases then converted to PAA by β-oxidation, after oral administration.
In monkeys following a single oral dose (600 mg PBA equivalents/kg) of [14C]glycerol phenylbutyrate:
● Tmax of PBA, PAA, and PAGN were 1.5, 8 and 8 h, respectively.
● Cmax of PBA, PAA, and PAGN were 52.2, 114 and 31.6 µg/mL, respectively.
In fasting healthy humans following a single oral administration of 6.43 g glycerol phenylbutyrate:
● Tmax of PBA, PAA and PAGN were 2.4, 4 and 4 h, respectively.
● Cmax of PBA, PAA and PAGN were 37.0, 14.9 and 30.2 µg/mL, respectively.
● PBA, PAA and PAGN showed half-life of 1.9, 1.4 and 5.9 h, respectively.
Distribution of Glycerol Phenylbutyrate
PBA and PAA exhibited low-to-high plasma protein binding in humans, mice, rats, rabbits and monkeys (6.6%-98.0%) with concentration dependent, but PAGN showed low in humans and monkeys (3.5%-12%) without concentration de-pendent.
In male monkeys following a single oral administration of glycerol phenylbutyrate: [4]
● The drug was widely distributed into most tissues.
● Relatively higher drug concentration levels were observed in large intestine, white bile, plasma, kidneys, liver, urinary bladder and whole blood at 8 h, compared to other organs.
Metabolism of Glycerol Phenylbutyrate
Could be metabolized in human liver and intestinal microsomes.
Glycerol phenylbutyrate was hydrolyzed to PBA by pancreatic lipases, and then β-oxidized to PAA after oral administration. After that PAA was conjugated with glutamine in the liver and in the kidneys through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN, and then eliminated in the urine.
Lipases in intestine and esterases in plasma were the major metabolizing enzymes. In vitro, relatively higher activity of lipases for glycerol phenylbutyrate was pancreatic triglyceride lipase followed by carboxyl ester lipase, and pancreatic lipase-related protein 2.
Excretion of Glycerol Phenylbutyrate
Was predominantly eliminated in urine in humans and monkeys, with PAGN as the most significant component in it.
Drug-Drug interaction
PBA was a potent inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 in vitro suggesting potential drug interaction in vivo by [I]/Ki for CYP2C9 and CYP2D6 >0.1, and [I]/IC50 for CYP3A4 >0.1.
PAA inhibited CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 at 20.7 mM.
Neither PBA nor PAA time-dependently inhibited human CYP enzyme in vitro.
Neither PBA nor PAA was an inducer of CYP1A2 and CYP3A4.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral administration studies in rats and monkeys:
● Rat MLD: 1.2 g/kg in males and 1.5 g/kg in females
● Monkey MLD: Not identified
Repeated-Dose Toxicity
Repeated-dose oral administration studies in mice (up to 13 weeks), rats (up to 6 months) and monkeys (up to 12 months):
● For mice: The NOAEL was 1.2 g/kg/day, determined by the 13-week toxicity study, and target organs of toxicity were central nervous system and increased the liver weight and produced hepatocellular hypertrophy.
● For rats: The NOAEL was not established and target organ of toxicity was central nervous system.
● For monkeys: The no effect dose was not identified, but the dose of 1.25 g/kg/day was close to or slightly higher than the maximum tolerated dose; Target organs of toxicity were central nervous system, increased liver weight (absolute and relative) in all treatment groups at weeks 26 and 52, and this change was associated with hepatocellular hypertrophy.
Safety Pharmacology
For conscious and unrestrained monkeys, significantly prolonged QTc interval by ~25 ms and slight shortening of the PR interval (8-14 ms)
The metabolites PBA at 894 µg/mL and PAA at 988 µg/mL inhibited hERG current by ~36% and 54%, respectively.
Genotoxicity
GT4P was not genotoxic in the Ames test, in vitro chromosomal aberration assay, or rat micronucleus assay.
The metabolite PBA was not genotoxic in the Ames assay, but significantly increased the proportion of cells with structural aberrations in the presence of S9 after 4 h treatment in an in vitro chromosome aberration test in Chinese hamster ovary (CHO) cells. However, the result was not reproducible in a repetition of this test in human lymphocytes.
Other metabolites including PAA, PAGN and PAG were not genotoxic in the Ames test or in vitro chromosomal aberration test.
Reproductive and Developmental Toxicity
In the fertility and general reproduction toxicity study in rats: Mating and parameters were unaffected, a small but statistically significant increase in embryo-lethality at 1.2 g/kg/day.
In the development toxicity study:
● For rabbits: Maternal toxicity and no effects on embryo-fetal development at 0.35 g/kg/day
● For rats: Maternal toxicity and adverse effects on embryo-fetal development (reduced fetal weights, and cervical ribs at the 7th cervical vertebra) at ≥0.65 g/kg/day
Pre- and postnatal reproduction toxicity in rats:
● For F0: Body weight gain reduced at 0.6 and 0.9 g/kg/day
● For F1: No treatment-related effects
Neonatal rat toxicity: Increased resumptions and reduced litter size
Carcinogenicity
26-week carcinogenicity study in Tg.rasH2 mice: No significant increase in tumor incidence
2-year carcinogenicity study in SD rats:
● For males at 0.65 g/kg/day: Significant increased in the incidence of pancreatic acinar cell adenoma, carcinoma and combined adenoma or carcinoma
● For females at 0.9 g/kg/day: Increased thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma.
● Not pose a carcinogenic risk for humans, and biphenyl was approved without carcinogenicity studies.
