2026/06/14 by Yoichi Wada, Mahoko Furujo, Kenichi Kashimada +10 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Adverse effect #Dialysis and Renal Disease Management #Discontinuation #Genomics and Rare Diseases #Glutamine #Metabolism and Genetic Disorders #Metabolite #Pharmacokinetics #Phenylbutyrate #Urea #Urea cycle
paper · doi:10.1002/jmd2.70082
openalex publication_date 2026/06/14 · openalex created_date 2026/06/15 · openalex updated_date 2026/08/01
ABSTRACT Sodium phenylbutyrate (NaPBA) is used for nitrogen scavenging in urea cycle disorders (UCDs), but its volume, palatability, and sodium load affect adherence and ammonia control. Glycerol phenylbutyrate (GPB) offers an alternative option with demonstrated improvements in metabolic control and palatability. For a Japanese perspective, we undertook an open‐label, multicentre, prospective Phase 3 study of efficacy, pharmacokinetics (PK), and safety. In a switch‐over, 15 patients received NaPBA for 7 days, then GPB for 7 days. Primary endpoint: 24‐h blood ammonia AUC (AUC NH3,0–24 ). Secondary endpoints: blood ammonia and glutamine concentration; PK of scavenger metabolites in blood and urine; safety. Patients then received GPB for up to 12 months. For GPB and NaPBA, respectively, mean (SD) AUC NH3,0–24 was 627 (198) and 757 (307) μmol·h/L (ratio 0.849; 95% CI 0.723–0.997). Mean peak and mean blood ammonia were 37 and 26 μmol/L versus 52 and 32 μmol/L. Mean plasma AUC 0–24 for phenylbutyrate (PBA), phenylacetate (PAA), and phenylacetylglutamine (PAGN) were 470, 1420, and 836 versus 425, 984, and 741 μg·h/mL. Mean PBA metabolite fluctuation was 297% versus 366%. One adverse event (hyperammonaemia) led to discontinuation in each treatment arm. In the extension ( n = 14), mean (SD) blood ammonia at Month 12 was 21 (8) μmol/L. No new safety findings were observed. GPB demonstrated effective control of blood ammonia with a favourable safety profile. It offers a practical and clinically advantageous alternative to NaPBA, extending previous evidence to Japanese individuals with UCDs. Trial registration: jRCT2071220110.