Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Immedica Pharma AB, SE-113 29, Stockholm, Sweden
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products
ATC code: A16AX09
Glycerol phenylbutyrate is a nitrogen-binding medicinal product. It is a triglyceride containing 3 molecules of PBA linked to a glycerol backbone.
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. Glycerol phenylbutyrate is hydrolysed by pancreatic lipases to yield, PBA, which is converted by beta oxidation to PAA, the active moiety of glycerol phenylbutyrate. 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. On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.
In the pooled analysis of studies where patients switched from sodium phenylbutyrate to glycerol phenylbutyrate, ammonia AUC0-24h was 774.11 and 991.19 [(micromol/L)*hour] during treatment with glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n=80, ratio of geometric means 0.84; 95% confidence intervals 0.740, 0.949).
The effect of multiple doses of glycerol phenylbutyrate 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomised, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects. The upper bound of the one-sided 95% CI for the largest placeboadjusted, baseline-corrected QTc, based on individual correction method (QTcI) for glycerol phenylbutyrate, was below 10 ms, demonstrating that glycerol phenylbutyrate had no QT/QTc prolonging effect. Assay sensitivity was confirmed by significant QTc prolongation of the positive control, moxifloxacin.
A randomised, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared equivalent doses of glycerol phenylbutyrate to sodium phenylbutyrate by evaluating 24-hour venous ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrolment for control of their UCD. Patients were required to have a diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have no clinical evidence of hyperammonaemia at enrolment and were not allowed to receive medicinal products known to increase ammonia levels (e.g. valproate), increase protein catabolism (e.g. corticosteroids), or significantly affect renal clearance (e.g. probenecid).
Glycerol phenylbutyrate was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 micromol/L*hour and 977 micromol/L*hour with glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n=44, ratio of geometric means 0.91; 95% confidence intervals 0.799, 1.034).
Consistent with plasma ammonia, blood glutamine levels were lower during glycerol phenylbutyrate treatment as compared with sodium phenylbutyrate in each arm of the crossover study (decrease of 44.3 ± 154.43 micromol/L after glycerol phenylbutyrate compared with NaPBA; p=0.064, paired t-test; p=0.048, Wilcoxon signed-rank test).
A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonaemic crisis over a 12-month period. A total of 51 adult patients involving deficiencies of CPS, OTC, ASS, ASL, ARG, and HHH were enrolled in the study and all but 6 had been converted from sodium phenylbutyrate to equivalent doses of glycerol phenylbutyrate. Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults in Study 2 were within normal limits during long-term treatment with glycerol phenylbutyrate (range: 6-30 micromol/L). Of 51 adult patients participating in Study 2, 7 patients (14%) reported a total of 10 hyperammonaemic crises during treatment with glycerol phenylbutyrate as compared with 9 patients (18%) who had reported a total of 15 crises in the 12 months prior to study entry while they were being treated with sodium phenylbutyrate.
The efficacy of glycerol phenylbutyrate in paediatric patients 2 months to 17 years of age involving deficiencies of OTC, ASS, ASL, and ARG was evaluated in 2 fixed sequence, open-label, sodium phenylbutyrate to equivalent dosing of glycerol phenylbutyrate switchover studies (Studies 3 and 4). Study 3 was 14 days in duration and Study 4 was 10 days in duration.
Glycerol phenylbutyrate was found to be non-inferior to sodium phenylbutyrate with respect to ammonia control in both of these paediatric studies. In the pooled analysis of the short-term studies in children (Study 3 and Study 4), plasma ammonia was significantly lower after switching to glycerol phenylbutyrate; ammonia AUC0-24h was 626.79 and 871.72 (micromol/L)*hour during treatment with glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n=26, ratio of geometric means 0.79; 95% confidence intervals 0.647, 0.955).
Mean blood glutamine levels were also non-significantly lower after glycerol phenylbutyrate treatment compared with sodium phenylbutyrate treatment by -45.2 ± 142.94 micromol/L (p=0.135, paired ttest; p=0.114, Wilcoxon signed-rank test).
Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonaemic crisis over a 12-month period in three studies (Study 2, which also enrolled adults, and extensions of Studies 3 and 4). A total of 49 children ages 2 months to 17 years with deficiencies of OTC, ASS, ASL, and ARG were enrolled, and all but 1 had been converted from sodium phenylbutyrate to glycerol phenylbutyrate. Mean fasting venous ammonia values were within normal limits during long-term treatment with glycerol phenylbutyrate (range: 17-25 micromol/L). Of the 49 paediatric patients who participated in these extension studies, 12 patients (25%) reported a total of 17 hyperammonaemic crises during treatment with glycerol phenylbutyrate as compared with 38 crises in 21 patients (43%) in the preceding 12 months prior to study entry, while they were being treated with sodium phenylbutyrate.
An open-label, long-term study (Study 5) was conducted to assess ammonia control in paediatric patients with UCD. The study enrolled a total of 45 paediatric patients between the ages of 1 and 17 years with UCD who had completed Study 2 and the safety extensions of Studies 3 and 4. The length of study participation ranged from 0.2 to 5.9 years. Venous ammonia levels were monitored at a minimum of every 6 months. Mean venous ammonia values in paediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with glycerol phenylbutyrate (range: 15-25 micromol/L). Of the 45 paediatric patients participating in the open-label treatment with glycerol phenylbutyrate, 11 patients (24%) reported a total of 22 hyperammonemic crises.
In an additional long term (24 month), uncontrolled, open-label clinical study the safety of RAVICTI has been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDs aged 2 months to less than 2 years.
A total of 16 paediatric patients with UCDs aged less than 2 months participated in a long-term (24 months), uncontrolled, open-label study, of which 10 patients converted from sodium phenylbutyrate to RAVICTI. Three patients were treatment naïve and three additional patients were gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while RAVICTI was initiated. All patients successfully transitioned to RAVICTI within 3 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 micromol/L. The mean normalized venous ammonia values in pediatric patients aged less than 2 months were within normal limits during long-term treatment with glycerol phenylbutyrate (range: 35 to 94 micromol/L).
Hyperammonaemia was reported in 5 (50%) subjects age <1 month (all serious but non-fatal) and 1 subject (16.7%) age 1-2 months (non-serious), which is consistent with more severe disease types diagnosed in the neonatal period. In 4 of the 5 subjects age <1 month, possible risk factors included infectious precipitants, hyperammonaemic crisis at baseline, and missing dose. No precipitant trigger or missing dose was reported for the other 2 subjects (1 age <1 month, 1 age 1-2-months). Dose adjustment was made to 3 subjects age <1 month.
A total of 10 paediatric patients with UCDs aged 2 months to less than 2 years participated in a long term (24 months) uncontrolled, open label study, of which 6 patients converted from sodium phenylbutyrate to RAVICTI and 1 patient converted from sodium phenylbutyrate and sodium benzoate. Two patients were treatment naïve and one additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while RAVICTI was initiated.
Nine patients successfully transitioned to RAVICTI within 4 days, followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 micromol/L. One additional patient developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on day 4. This patient developed hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.
Three patients reported a total of 7 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high venous ammonia levels and requiring medical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). There was one additional patient who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.
ADRs are summarised in Section 4.8.
Reversal of the pre-existing neurological impairment is unlikely following treatment and neurological deterioration may continue in some patients.
RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by pancreatic lipases. PBA derived from glycerol phenylbutyrate is further converted by β-oxidation to PAA.
In healthy, fasting adult subjects receiving a single oral dose of 2.9 ml/m² of glycerol phenylbutyrate, peak plasma levels of PBA, PAA, and PAGN occurred at 2 h, 4 h, and 4 h, respectively. Upon singledose administration of glycerol phenylbutyrate, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time post dose (0.25 h). Mean maximum concentration (Cmax) for PBA, PAA, and PAGN was 37.0 micrograms/ml, 14.9 micrograms/ml, and 30.2 micrograms/ml, respectively. In healthy subjects, intact glycerol phenylbutyrate was not detected in plasma.
In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose dependent manner. Following 4 ml of glycerol phenylbutyrate for 3 days (3 times a day [TID]), mean Cmax and AUC were 66 mcg/ml and 930 mcg•h/ml for PBA and 28 microgram/ml and 942 mcg•h/ml for PAA, respectively. In the same study, following 6 ml of glycerol phenylbutyrate for 3 days (TID), mean Cmax and AUC were 100 mcg/ml and 1400 mcg•h/ml for PBA and 65 mcg/ml and 2064 mcg•h/ml for PAA, respectively.
In adult UCD patients receiving multiple doses of glycerol phenylbutyrate, maximum plasma concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in UCD patients.
Population pharmacokinetic modelling and dosing simulations suggest that PBA enters the circulation about 70-75% more slowly when given orally as glycerol phenylbutyrate as compared with sodium phenylbutyrate and further indicate that body surface area is the most significant covariate explaining the variability of PAA clearance.
In vitro, the extent of human plasma protein binding for 14C-labeled metabolites was 80.6% to 98.0% for PBA (over 1-250 microgram/ml), and 37.1% to 65.6% for PAA (over 5-500 microgram /ml). The protein binding for PAGN was 7% to 12% and no concentration effects were noted.
Upon oral administration, pancreatic lipases hydrolyse glycerol phenylbutyrate and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: Lglutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.
Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.
In healthy subjects, after administration of 4 ml, 6 ml, and 9 ml 3 times daily for 3 days, the ratio of mean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean values for PAA to PAGN among all patients dosed with 6 ml and 9 ml twice daily ranged from 0.96 to 1.28 and for patients dosed with 9 ml twice daily ranged from 1.18-3.19.
In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was seen in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, glycerol phenylbutyrate was hydrolysed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans.
The mean (SD) percentage of administered PBA eliminated as PAGN was approximately 68.9% (17.2) in adults and 66.4% (23.9) in paediatric UCD patients at steady state. PAA and PBA represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA.
In a study in patients with clinically decompensated cirrhosis and hepatic encephalopathy (Child-Pugh B and C), mean Cmax of PAA was 144 mcg/ml (range: 14-358 mcg/ml) after daily dosing of 6 ml of glycerol phenylbutyrate twice daily, while mean Cmax of PAA was 292 mcg/ml (range: 57-655 mcg/ml) after daily dosing of 9 ml of glycerol phenylbutyrate twice daily. The ratio of mean values for PAA to PAGN among all patients dosed with 6 ml BID ranged from 0.96 to 1.28 and for patients dosed with 9 ml twice daily ranged from 1.18-3.19.After multiple doses, a PAA concentration >200 mcg/L was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5.
These findings collectively indicate that conversion of PAA to PAGN may be impaired in patients with severe hepatic impairment and that a plasma PAA to PAGN ratio >2.5 identifies patients at risk of elevated PAA levels.
The pharmacokinetics of glycerol phenylbutyrate in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on haemodialysis, have not been studied.
In healthy adult volunteers, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female volunteers, mean Cmax for PAA was 51% and 120% higher than in male volunteers after administration of 4 ml and 6 ml 3 times daily for 3 days, respectively. The dose normalized mean AUC0-23h for PAA was 108% higher in females than in males. However, dosing in UCD patients must be individualized based on the specific metabolic needs and residual enzyme capacity of the patient, irrespective of gender.
Population pharmacokinetic modelling and dosing simulations suggest body surface area is the most significant covariate explaining the variability of PAA clearance. PAA clearance was 7.1 L/h, 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for UCD patients ages ≤2, 3 to 5, 6 to 11, and 12 to 17 years. In 16 paediatric UCD patients aged less than 2 months, PAA clearance was 3.8 L/h. In 7 paediatric patients aged 2 months to under 2 years of age who received RAVICTI for up to 12 months, the concentrations of PAA, PBA, and PAGN did not increase over the treatment period and the overall median PAA, PBA, and PAGN concentrations in these patients were similar to those observed in older paediatric age groups.
The mean peak ratio of PAA to PAGN in UCD patients aged birth to less than 2 months was higher (mean: 1.65; range 0.14 to 7.07) than for UCD patients aged 2 months to less than 2 years (mean 0.59; range 0.17 to 1.21). No PAA toxicity was observed in the subjects age <2 months.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In a rat study, glycerol phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma in males and females, at a dose of 4.7 and 8.4 times the dose in adult patients, (6.87 ml/m²/day based on combined AUCs for PBA and PAA). The incidence of the following tumours was also increased in female rats: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, cervical schwannoma, uterine endometrial stromal polyp, and combined polyp or sarcoma.
Glycerol phenylbutyrate was not tumourigenic at doses up to 1000 mg/kg/day in a 26-week mouse study.
Glycerol phenylbutyrate has been tested in a range of in vitro and in vivo genotoxicity studies, and shown no genotoxic activity.
Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats at clinical exposure levels, however at oral doses up to approximately 7 times the dose in adult patients, maternal as well as male toxicity was observed and the number of nonviable embryos was increased.
Oral administration of glycerol phenylbutyrate during the period of organogenesis in rats and rabbits had no effects on embryo-foetal development at 2.7 and 1.9 times the dose in adult patients, respectively. However, maternal toxicity and adverse effects on embryo-foetal development including reduced foetal weights and cervical ribs were observed in a rat study with a dose approximately 6 times the dose in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities were observed in rats through day 92 postpartum following oral administration in pregnant rats, during organogenesis and lactation.
In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced in males and females, by up to 16% and 12% respectively. Fertility (number of pregnant rats) was decreased by up to 25%, at a dose of 2.6 times the dose in adult patients. Embryo toxicity (increased resorptions) and reduced litter size was also observed.
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