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 ∼30% lower than on NaPBA (time-normalized AUC = 26.2 vs. 38.4 μmol/L; Cmax = 56.3 vs. 79.1 μmol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC0-24) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 μg h/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 μg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 μg h/mL) were similar. Urinary PAGN excretion accounted for ∼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.
- Clinical trial
- Urea cycle disorders