Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate

被引：73

作者：

Diaz, George A. ^{[1
]}

Krivitzky, Lauren S. ^{[2
]}

Mokhtarani, Masoud ^{[3
]}

Rhead, William ^{[4
]}

Bartley, James ^{[5
]}

Feigenbaum, Annette ^{[6
]}

Longo, Nicola ^{[7
]}

Berquist, William ^{[8
]}

Berry, Susan A. ^{[9
]}

Gallagher, Renata ^{[10
]}

Lichter-Konecki, Uta ^{[11
]}

Bartholomew, Dennis ^{[12
]}

Harding, Cary O. ^{[13
]}

Cederbaum, Stephen ^{[14
]}

McCandless, Shawn E. ^{[15
]}

Smith, Wendy ^{[16
]}

Vockley, Gerald ^{[17
]}

Bart, Stephen A. ^{[18
]}

Korson, Mark S. ^{[19
]}

Kronn, David ^{[20
]}

Zori, Roberto ^{[21
]}

Merritt, J. Lawrence, II ^{[22
]}

Nagamani, Sandesh C. S. ^{[23
]}

Mauney, Joseph ^{[24
]}

LeMons, Cynthia

Dickinson, Klara ^{[3
]}

Moors, Tristen L. ^{[3
]}

Coakley, Dion F. ^{[3
]}

Scharschmidt, Bruce F. ^{[3
]}

Lee, Brendan ^{[23
]}

机构：

[1] Mt Sinai Sch Med, Dept Genet & Genom Sci, Dept Pediat, New York, NY USA

[2] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[3] Hyper Therapeut, San Francisco, CA USA

[4] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[5] Long Beach Mem Hosp Med Ctr, Long Beach, CA USA

[6] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[7] Univ Utah, Salt Lake City, UT USA

[8] Stanford Univ, Palo Alto, CA 94304 USA

[9] Univ Minnesota, Minneapolis, MN USA

[10] Childrens Hosp Colorado, Aurora, CO USA

[11] Childrens Natl Med Ctr, Washington, DC 20010 USA

[12] Nationwide Childrens Hosp, Columbus, OH USA

[13] Oregon Hlth & Sci Univ, Portland, OR USA

[14] Univ Calif Los Angeles, Los Angeles, CA USA

[15] Case Western Reserve Univ, Cleveland, OH 44106 USA

[16] Maine Med Ctr, Portland, ME 04102 USA

[17] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA

[18] SNBL, Baltimore, MD USA

[19] Tufts Med Ctr, Boston, MA USA

[20] Westchester Med Ctr, Valhalla, NY USA

[21] Univ Florida, Gainesville, FL USA

[22] Seattle Childrens Hosp, Seattle, WA USA

[23] Baylor Coll Med, Houston, TX 77030 USA

[24] Chiltern, Wilmington, NC USA

来源：

HEPATOLOGY | 2013年 / 57卷 / 06期

关键词：

SODIUM PHENYLBUTYRATE; CLINICAL-TRIALS; DEFICIENCY; CHILDREN; SAFETY;

D O I：

10.1002/hep.26058

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 (NH3-AUC0-24hr), 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) NH3-AUC0-24hr of 866 (661) versus 977 (865) mol center dot 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, NH3-AUC0-24hr 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). (HEPATOLOGY 2012)

引用

页码：2171 / 2179

页数：9

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