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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01347073.

Copyright © 2013 Mosby, Inc. All rights reserved.

Figures

Figure

Ammonia and metabolite levels during treatment with glycerol phenylbutyrate (GPB) and sodium phenylbutyrate (NaPBA). A, Mean +/− SD ammonia levels during treatment with GPB or NaPBA at several time points over 24 hours. B, Mean +/− SD plasma levels of phenylbutyric acid (PBA), phenylacetic acid (PAA) and phenylacetyl glutamine (PAGN) as well as urinary concentrations of PAGN. The limit of quantitation, shown by the dashed line, is 1 µg/mL. Systemic PBA exposure did not differ significantly between the two drugs (mean (SD) AUC0–24 = 255 (54.5) vs. 483 (146.0) µg•h/mL on GPB and NaPBA, respectively). Mean systemic PAA and PAGN exposure were also similar for the two drugs (mean (SD) AUC0–24 for PAA = 1096 (214.0) vs. 1458 (211.3) µg•h/mL for GPB and NaPBA, respectively; mean (SD) AUC0–24 for PAGN = 1130 (71.2) vs. 946 (75.5) µg•h/mL for GPB and NaPBA, respectively). Urinary PAGN concentration at 0 hr = 11030 (101) on GPB and 5847 (143) on NaPBA; PAGN:creatinine concentration ratio at 0 hr = 18.8 on GPB and 11.9 on NaPBA, p-value = 0.01; urinary PAGN concentration at 24 hr = 16688 (57) on GPB and 9901 (96) on NaPBA; PAGN:creatinine concentration ratio at 24 hr = 23.4 on GPB and 13.2 on NaPBA, p-value = 0.045) and generally similar at the 12 hour time points (urinary PAGN at 12 hr = 14134 (76) on GPB and 13900 (105) on NaPBA; PAGN:creatinine concentration ratio = 41.4 on GBP and 33.3 on NaPBA, p-value = 0.77).