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

Susan A. Berry, Jerry Vockley, Alexander A. Vinks, Min Dong, George A. Diaz, Shawn E. McCandless, Wendy E. Smith, Cary Harding, Roberto Zori, Can Ficicioglu, Uta Lichter-Konecki, Renee Perdok, Beth Robinson, Robert J. Holt, Nicola Longo

Research output: Contribution to journalArticle

Abstract

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)251-257
Number of pages7
JournalMolecular Genetics and Metabolism
Volume125
Issue number3
DOIs
StatePublished - Nov 1 2018

Fingerprint

Inborn Urea Cycle Disorder
Pediatrics
Pharmacokinetics
Urea
Acids
Lipase
Nitrogen
Body Surface Area
Prodrugs
Glutamine
Plasmas
Dietary Proteins
Scavenging
glycerol phenylbutyrate
phenylacetic acid
Labels
Hydrolysis
Amino Acids

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders. / Berry, Susan A.; Vockley, Jerry; Vinks, Alexander A.; Dong, Min; Diaz, George A.; McCandless, Shawn E.; Smith, Wendy E.; Harding, Cary; Zori, Roberto; Ficicioglu, Can; Lichter-Konecki, Uta; Perdok, Renee; Robinson, Beth; Holt, Robert J.; Longo, Nicola.

In: Molecular Genetics and Metabolism, Vol. 125, No. 3, 01.11.2018, p. 251-257.

Research output: Contribution to journalArticle

Berry, SA, Vockley, J, Vinks, AA, Dong, M, Diaz, GA, McCandless, SE, Smith, WE, Harding, C, Zori, R, Ficicioglu, C, Lichter-Konecki, U, Perdok, R, Robinson, B, Holt, RJ & Longo, N 2018, 'Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders', Molecular Genetics and Metabolism, vol. 125, no. 3, pp. 251-257. https://doi.org/10.1016/j.ymgme.2018.09.001
Berry, Susan A. ; Vockley, Jerry ; Vinks, Alexander A. ; Dong, Min ; Diaz, George A. ; McCandless, Shawn E. ; Smith, Wendy E. ; Harding, Cary ; Zori, Roberto ; Ficicioglu, Can ; Lichter-Konecki, Uta ; Perdok, Renee ; Robinson, Beth ; Holt, Robert J. ; Longo, Nicola. / Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders. In: Molecular Genetics and Metabolism. 2018 ; Vol. 125, No. 3. pp. 251-257.
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abstract = "Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.",
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T1 - Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders

AU - Berry, Susan A.

AU - Vockley, Jerry

AU - Vinks, Alexander A.

AU - Dong, Min

AU - Diaz, George A.

AU - McCandless, Shawn E.

AU - Smith, Wendy E.

AU - Harding, Cary

AU - Zori, Roberto

AU - Ficicioglu, Can

AU - Lichter-Konecki, Uta

AU - Perdok, Renee

AU - Robinson, Beth

AU - Holt, Robert J.

AU - Longo, Nicola

PY - 2018/11/1

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N2 - Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

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