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Mol Genet Metab. 2018 Nov;125(3):251-257. doi: 10.1016/j.ymgme.2018.09.001. Epub 2018 Sep 4.

Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders.

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University of Minnesota Department of Pediatrics, Minneapolis, MN, USA.
University of Pittsburgh School of Medicine and the Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
Maine Medical Center, Portland, ME, USA.
Oregon Health & Science University, Portland, OR, USA.
University of Florida, Gainesville, FL, USA.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Horizon Pharma USA, Inc, Lake Forest, IL, USA.
Horizon Pharma USA, Inc, Lake Forest, IL, USA; University of Illinois-Chicago, Chicago, IL, USA. Electronic address:
University of Utah, Salt Lake City, UT, USA.



Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2 months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN). Pharmacokinetics (PK) of GPB were examined to see if hydrolysis is impaired in very young patients who may lack lipase activity.


Patients 2 months to <2 years of age with UCDs from two open label studies (n = 17, median age 10 months) predominantly on stable doses of nitrogen scavengers (n = 14) were switched to GPB. Primary assessments included traditional plasma PK analyses of PBA, PAA, and PAGN, using noncompartmental methods with WinNonlin™. UPAGN was collected periodically throughout the study up to 12 months.


PBA, PAA and PAGN rapidly appeared in plasma after GPB dosing, demonstrating evidence of GPB cleavage with subsequent PBA absorption. Median concentrations of PBA, PAA and PAGN did not increase over time and were similar to or lower than the values observed in older UCD patients. The median PAA/PAGN ratio was well below one over time, demonstrating that conjugation of PAA with glutamine to form PAGN did not reach saturation. Covariate analyses indicated that age did not influence the PK parameters, with body surface area (BSA) being the most significant covariate, reinforcing current BSA based dosing recommendations as seen in older patients.


These observations demonstrate that UCD patients aged 2 months to <2 years have sufficient lipase activity to adequately convert the pre-prodrug GPB to PBA. PBA is then converted to its active moiety (PAA) providing successful nitrogen scavenging even in very young children.


Children; Glycerol phenylbutyrate; Infants; Pharmacokinetics; Urea cycle disorders

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