Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials.

BACKGROUND: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. METHODS: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). RESULTS: After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. CONCLUSIONS: The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.

UNLABELLED: Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. CONCLUSION: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).

Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.

UNLABELLED: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) µmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved. CONCLUSION: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).

Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate.

OBJECTIVES: To examine ammonia levels, pharmacokinetics, and safety of glycerol phenylbutyrate (GPB; also referred to as HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs). STUDY DESIGN: This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hour blood and urine sampling on NaPBA and again on a phenylbutyric acid-equimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD. RESULTS: Fifteen patients (8 argininosuccinate lyase deficiency, 3 argininosuccinic acid synthetase deficiency, 3 ornithine transcarbamylase deficiency, 1 arginase deficiency) ages 2 months through 5 years enrolled in and completed the study. Daily ammonia exposure (24-hour area under the curve) was lower on GPB and met predefined noninferiority criteria (ratio of means 0.79; 95% CI 0.593-1.055; P=.03 Wilcoxon; 0.07 t test). Six patients experienced mild adverse events on GPB; there were no serious adverse events or significant laboratory changes. Liver tests and argininosuccinic acid levels among patients with argininosuccinate lyase deficiency were unchanged or improved on GPB. Eleven of 15 patients reported 35 symptoms on day 1; 23 of these 35 symptoms improved or resolved on GPB. Mean systemic exposure to phenylbutyric acid, phenylacetic acid, and phenylacetylglutamine (PAGN) were similar and phenylacetic acid exposure tended to be higher in the youngest children on both drugs. Urinary PAGN concentration was greater on morning voids and varied less over 24 hours on GPB versus NaPBA. CONCLUSIONS: GPB results in more evenly distributed urinary output of PAGN over 24 hours were associated with fewer symptoms and offers ammonia control comparable with that observed with NaPBA in young children with UCDs.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

UNLABELLED: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. CONCLUSION: GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.

Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control.

UNLABELLED: Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia. METHODS: An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA). RESULTS: Ten subjects completed the study. Adverse events were comparable for the two drugs; 2 subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 54% of PBA administered for both NaPBA and GPB; other metabolites accounted for <1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=-0.82; p<0.0001) but weakly or not at all with blood metabolite levels. CONCLUSIONS: Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.

Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives.

UNLABELLED: Patients and families living with metabolic disorders face challenging dietary and drug treatment regimens. On the hypothesis that poor palatability, volume and frequency of drug/formula administration contribute to treatment non-adherence and hyperammonemic episodes, a survey was conducted of patient, caregiver (CG) and physician perspectives on treatments used in urea cycle disorders (UCD). METHODS: A paper and online survey assessed experience with UCD medications, medical foods and dietary supplements. RESULTS: 25 physicians, 52 adult patients and 114 CG responded. In 2009, the most common UCD-specific intervention reported by patients included sodium phenylbutyrate (60%), followed by l-citrulline (46%), amino acid medical foods (15%), l-arginine preparations (18%), and sodium benzoate (8%). Only 36% of patients reported experiencing no hyperammonemic episodes in the last 2 years. The most commonly reported cause of hyperammonemic episodes was infection or other acute illnesses, followed by dietary indiscretion, side effects of medications, and drug non-adherence. Most patients, caregivers and physicians (> 75%) ranked nitrogen-scavenging medications, l-citrulline, l-arginine, and medical foods as "effective" or "very effective." Non-adherence was common (e.g. 18% of patients admitted to missing sodium phenylbutyrate "at least once a week" and "at least one a day"). Barriers to adherence included taste of medications, frequency of drug administration, number of pills, difficulty swallowing pills, side effects, forgetting to take medications, and high cost. Strategies to mitigate the gastrointestinal side effects of medications included the use of gastric tubes and acid reflux medications. Physicians indicated that 25% and 33% of pediatric and adult patients, respectively, were given less than the recommended dose of sodium phenylbutyrate due to concerns of tolerance, administration, and cost. CONCLUSIONS: Despite positive views of their effectiveness, respondents found medications, medical foods and dietary supplements difficult to take and viewed adherence as inadequate, thus contributing to hyperammonemic episodes.

Glycerol Phenylbutyrate in Patients With Cirrhosis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous Ammonia Concentration.

Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6 mL (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4 (27.9) µmol/L (ULN ∼48 µmol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cmax of 144 [125] vs. 292 [224] µg/mL on 6 and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9 mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE.