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Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate
Author(s) -
Diaz George A.,
Krivitzky Lauren S.,
Mokhtarani Masoud,
Rhead William,
Bartley James,
Feigenbaum Annette,
Longo Nicola,
Berquist William,
Berry Susan A.,
Gallagher Renata,
LichterKonecki Uta,
Bartholomew Dennis,
Harding Cary O.,
Cederbaum Stephen,
McCandless Shawn E.,
Smith Wendy,
Vockley Gerald,
Bart Stephen A.,
Korson Mark S.,
Kronn David,
Zori Roberto,
Merritt J. Lawrence,
C.S. Nagamani Sandesh,
Mauney Joseph,
LeMons Cynthia,
Dickinson Klara,
Moors Tristen L.,
Coakley Dion F.,
Scharschmidt Bruce F.,
Lee Brendan
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26058
Subject(s) - phenylbutyrate , urea cycle , glycerol , medicine , hyperammonemia , chemistry , endocrinology , biochemistry , arginine , amino acid
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 (NH 3 ‐AUC 0‐24hr ), 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) NH 3 ‐AUC 0‐24hr 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, NH 3 ‐AUC 0‐24hr 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). (H EPATOLOGY 2012)