General Information

Ravicti (glycerol phenylbutyrate) is a nitrogen-binding agent. Urea cycle disorders result from deficiencies in the enzymes responsible for clearing toxic ammonia from the blood. During protein metabolism, nitrogen is produced as a waste product, which is normally converted to urea and excreted. In patients with urea cycle disorders, the nitrogen accumulates as ammonia and can cause coma, brain damage, and death. Glycerol phenylbutyrate aids in the removal of this accumulated ammonia.

Ravicti is specifically indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients over 2 years of age with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements.

Ravicti is supplied as a liquid for oral administration. It should be taken with food and administered directly into the mouth via oral syringe or dosing cup. The recommended dosages for patients switching from sodium phenylbutyrate to Ravicti and patients naïve to phenylbutyric acid are different. For both subpopulations:
Give Ravicti in three equally divided dosages, each rounded up to the nearest 0.5 mL.
The maximum total daily dosage is 17.5 mL (19 g).
Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements.

Please see the Ravicti drug label for specific instructions in dosing patients switching from sodium phenylbutyrate to Ravicti and patients naïve to phenylbutyric acid.

Clinical Results

FDA Approval
The FDA approval of Ravicti was based on separate studies in adults and pediatrics.
Clinical Studies in Adults
A randomized, double-blind, active-controlled, crossover, non-inferiority study enrolled 45 subjects with UCDs who had been on sodium phenylbutyrate prior to enrollment. The trial was designed to compare Ravicti to sodium phenylbutyrate by evaluating venous ammonia levels. The primary endpoint was to establish non-inferiority in the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. The subjects were randomized to Sodium phenylbutyrate for 2 weeks followed by Ravicti for 2 weeks or Ravicti for 2 weeks followed by Sodium phenylbutyrate for 2 weeks. The dose of Ravicti was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the trial. Both treatments were administered three times daily with meals. Forty-four subjects were evaluable for analysis. Ravicti was noninferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 µmol/L hour and 977 µmol/L hour with Ravicti and sodium phenylbutyrate, respectively.
Long-term (12-month), uncontrolled, open-label study
This study was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Ravicti. Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults were within normal limits during long-term treatment with Ravicti (range: 6-30 µmol/L). Of 51 adult, 7 (14%) reported a total of 10 hyperammonemic crises.
Clinical Studies in Pediatrics
Two fixed-sequence, open-label, sodium phenylbutyrate to Ravicti switchover studies were conducted in pediatrics ages 2 to 17 years. The first study was 7 days in duration and the second study was 10 days in duration. A total of 26 subjects were enrolled. The dose of Ravicti was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate patients were taking when they entered the trial. Sodium phenylbutyrate or Ravicti were administered in divided doses with meals and the subjects adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all subjects underwent 24 hours of venous ammonia measurements, as well as blood and urine PK assessments. The 24-hour AUCs for blood ammonia (AUC0-24h) in 11 pediatrics 6 to 17 years of age (Study 1) and 11 pediatrics 2 years to 5 years of age (Study 2) were similar between treatments. In children 6 to 17 years of age, the ammonia AUC0-24h was 604 µmol·h/L vs. 815 µmol·h/L on Ravicti versus sodium phenylbutyrate. In the patients between 2 years and 5 years of age, the ammonia AUC0-24h was 632 µmol·h/L vs. 720 µmol·h/L on Ravicto versus sodium phenylbutyrate.
Long-term (12-month), uncontrolled, open-label studies
These studies were conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. In two studies, on of which also enrolled adults (see above), and an extension of Study 1 above, referred to here as Study 1E), a total of 26 children ages 6 to 17, were enrolled, and all but 1 had been converted from sodium phenylbutyrate to Ravicti. Mean fasting venous ammonia values were within normal limits during long-term treatment with Ravicti (range: 17-23 µmol/L). Of the 26 patients, 5 (19%) reported a total of 5 hyperammonemic crises. In an extension of Study 2, after a median time on study of 4.5 months (range 1.0-5.7 months), 2 of 16 pediatrics ages 2 to 5 years had experienced three hyperammonemic crises.

Mechanism of Action

Ravicti (glycerol phenylbutyrate) is a nitrogen-binding agent. UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH3, NH4+). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Ravicti is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Ravicti. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Literature References

Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, Lemons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate. The Journal of Pediatrics 2013 Jan 13. pii: S0022-3476(12)01418-7

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology 2012 Sep 7. doi: 10.1002/hep.26058