Background: Ammunol (sodium phenylacetate/sodium benzoate) is an intravenously administered, investigational drug used for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. A pharmacokinetic study of sodium phenylacetate/sodium benzoate (NAPA/NABZ) was performed in two groups of normal healthy volunteers, following the dosing regimen used to treat hyperammonemia.
Methods: The first group of subjects (n = 3) received a bolus dose of 5.5 g/m2 of NAPA/NABZ, over a period of 1.5 h. Following a seven-day washout, subjects then received the same bolus dose, followed by a continuous infusion of 5.5 g/m2 over 24h. A second group of different subjects (n = 17) received the same treatment regimen, but using doses of 3.75 g/m2. Phenylacetate (PA) and benzoate (BZ), and their respective metabolites, phenylacetylglutamine (PAG), and hippurate (HIP) were measured over a 24-h period. An HPLC method was used for the measurement of all analyte concentrations. Non-compartmental analysis and modeling was performed using WinNonlin Professional.
Results: Both BZ and PA displayed saturable, non-linear elimination, with a decrease in clearance with increased dose. During the bolus dose with continuous infusion regimen, plasma levels of both BZ and PA peaked at the end of the priming dose, and PA levels remained near peak for 5-9h. In contrast, BZ plasma levels immediately fell following the priming dose, and became undetectable at 14.1+/-4.2 and 26.8+/-2.3h in the low- and high-dose group, respectively. The formation of HIP occurred more rapidly than that of PAG. For both PA and BZ, metabolite formation increased in a linear fashion with the dose.
Conclusion: These data describe the pharmacokinetics of PA and BZ, and their respective metabolites, as observed in healthy adult volunteers, with the higher dose studied equivalent to that used to treat hyperammonemia. Dose optimization is required to maximize nitrogen removal, while minimizing the risk of toxicity, especially due to PA. Because of the slower elimination of PA, and the non-linear pharmacokinetic behavior displayed by both PA and BZ, only investigational protocol-specific doses should be used, and higher doses should be avoided unless blood level monitoring can be done promptly and frequently.