This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of Buphenyl? (sodium phenylbutyrate) with citrulline or arginine. Although an effective treatment, Buphenyl? has some disadvantages, such as a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20 kg child), unpleasant taste, and high sodium content. There is some evidence from clinical trials of PBA for other indications that the high pill burden may decrease the likelihood of compliance with the treatment regimen. Glyceryl tri (4-phenylbutyrate) (GT4P or HPN-100), a prodrug of phenylbutyrate (PBA) (Buphenyl?) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl? in patients with UCDs. HPN-100 is expected to provide similar nitrogen-scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden. This is the first study of HPN-100 in pediatric subjects with UCDs and is a fixed-sequence, open-label, switch-over study of HPN-100 designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with NaPBA. Subjects will receive NaPBA three times daily for one week and then receive the same PBA mole-equivalent dose of HPN-100 for one week and compare the safety and pharmacokinetic (PK) characteristics of the two treatment arms. The switch-over part of the study is followed with a 12-month extension. Eligible subjects who complete the switch-over section will be offered an opportunity to enroll in the safety extension during which they will be assessed monthly to evaluate the long-term safety of HPN-100 and its control of blood ammonia in pediatric subjects with UCDs. I. HYPOTHESIS HPN-100 will be a safe, well-tolerated alternative to Buphenyl? for pediatric patients (age 6-17 yrs) with urea cycle disorders. II.
SPECIFIC AIMS The primary objective of the 2-week switch over period of the study is to evaluate the safety and PK characteristics of HPN-100 as compared to NaPBA in pediatric subjects with UCDs. The secondary objective is to evaluate control of blood ammonia by HPN-100 as compared to NaPBA in pediatric subjects with UCDs.
The specific aim of the extension part of the study is to evaluate the long-term safety of HPN-100 and its control of blood ammonia in pediatric subjects with UCDs.
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