Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer

Patrick Thompson, Frank Balis, Baruti M. Serabe, Stacey Berg, Peter Adamson, Renee Klenke, Alberta Aiken, Roger Packer, Daryl J. Murry, Regina Jakacki, Susan M. Blaney

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer. Methods: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection. Results: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55 ± 18 min at the 1.8 g/m2 dose and 77 ± 22 min at the 2.5 g/m2 dose. The half-life of PAG was 112 ± 53 min at the 1.8 g/m2 dose and 135 ± 75 min at the 2.5 g/m2 dose. The clearance of PAA was 66 ± 33 ml/min per m2 at the 1.8 g/m2 dose and 60 ± 24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means ± SD) 18.4 ± 13.8 mg/m2 per min and 152 ± 155 μg/ml, respectively. The volumes of distribution for PAA and PAG (V d-PAA and Vd-PAG) were 7.9 ± 3.4 l/m2 and 34.4 ± 16.1 l/m2, respectively. The first-order elimination rate constant for PAG (ke-PAG) was 0.0091 ± 0. 0039 min-1. Conclusions: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.

Original languageEnglish (US)
Pages (from-to)417-423
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume52
Issue number5
DOIs
StatePublished - Nov 1 2003

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Pharmacokinetics
Refractory materials
Neoplasms
Metabolites
phenylacetic acid
Half-Life
Tumors
phenylacetylglutamine
High performance liquid chromatography
Reverse-Phase Chromatography
Phenylalanine
Rate constants
Assays

Keywords

  • Pediatric
  • Pharmacokinetic
  • Phenylacetate
  • Phenylacetylglutamine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Thompson, P., Balis, F., Serabe, B. M., Berg, S., Adamson, P., Klenke, R., ... Blaney, S. M. (2003). Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer. Cancer Chemotherapy and Pharmacology, 52(5), 417-423. https://doi.org/10.1007/s00280-003-0674-0

Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer. / Thompson, Patrick; Balis, Frank; Serabe, Baruti M.; Berg, Stacey; Adamson, Peter; Klenke, Renee; Aiken, Alberta; Packer, Roger; Murry, Daryl J.; Jakacki, Regina; Blaney, Susan M.

In: Cancer Chemotherapy and Pharmacology, Vol. 52, No. 5, 01.11.2003, p. 417-423.

Research output: Contribution to journalArticle

Thompson, P, Balis, F, Serabe, BM, Berg, S, Adamson, P, Klenke, R, Aiken, A, Packer, R, Murry, DJ, Jakacki, R & Blaney, SM 2003, 'Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer', Cancer Chemotherapy and Pharmacology, vol. 52, no. 5, pp. 417-423. https://doi.org/10.1007/s00280-003-0674-0
Thompson, Patrick ; Balis, Frank ; Serabe, Baruti M. ; Berg, Stacey ; Adamson, Peter ; Klenke, Renee ; Aiken, Alberta ; Packer, Roger ; Murry, Daryl J. ; Jakacki, Regina ; Blaney, Susan M. / Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer. In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 52, No. 5. pp. 417-423.
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abstract = "Purpose: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer. Methods: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection. Results: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55 ± 18 min at the 1.8 g/m2 dose and 77 ± 22 min at the 2.5 g/m2 dose. The half-life of PAG was 112 ± 53 min at the 1.8 g/m2 dose and 135 ± 75 min at the 2.5 g/m2 dose. The clearance of PAA was 66 ± 33 ml/min per m2 at the 1.8 g/m2 dose and 60 ± 24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means ± SD) 18.4 ± 13.8 mg/m2 per min and 152 ± 155 μg/ml, respectively. The volumes of distribution for PAA and PAG (V d-PAA and Vd-PAG) were 7.9 ± 3.4 l/m2 and 34.4 ± 16.1 l/m2, respectively. The first-order elimination rate constant for PAG (ke-PAG) was 0.0091 ± 0. 0039 min-1. Conclusions: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.",
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T1 - Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer

AU - Thompson, Patrick

AU - Balis, Frank

AU - Serabe, Baruti M.

AU - Berg, Stacey

AU - Adamson, Peter

AU - Klenke, Renee

AU - Aiken, Alberta

AU - Packer, Roger

AU - Murry, Daryl J.

AU - Jakacki, Regina

AU - Blaney, Susan M.

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Purpose: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer. Methods: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection. Results: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55 ± 18 min at the 1.8 g/m2 dose and 77 ± 22 min at the 2.5 g/m2 dose. The half-life of PAG was 112 ± 53 min at the 1.8 g/m2 dose and 135 ± 75 min at the 2.5 g/m2 dose. The clearance of PAA was 66 ± 33 ml/min per m2 at the 1.8 g/m2 dose and 60 ± 24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means ± SD) 18.4 ± 13.8 mg/m2 per min and 152 ± 155 μg/ml, respectively. The volumes of distribution for PAA and PAG (V d-PAA and Vd-PAG) were 7.9 ± 3.4 l/m2 and 34.4 ± 16.1 l/m2, respectively. The first-order elimination rate constant for PAG (ke-PAG) was 0.0091 ± 0. 0039 min-1. Conclusions: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.

AB - Purpose: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer. Methods: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection. Results: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55 ± 18 min at the 1.8 g/m2 dose and 77 ± 22 min at the 2.5 g/m2 dose. The half-life of PAG was 112 ± 53 min at the 1.8 g/m2 dose and 135 ± 75 min at the 2.5 g/m2 dose. The clearance of PAA was 66 ± 33 ml/min per m2 at the 1.8 g/m2 dose and 60 ± 24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means ± SD) 18.4 ± 13.8 mg/m2 per min and 152 ± 155 μg/ml, respectively. The volumes of distribution for PAA and PAG (V d-PAA and Vd-PAG) were 7.9 ± 3.4 l/m2 and 34.4 ± 16.1 l/m2, respectively. The first-order elimination rate constant for PAG (ke-PAG) was 0.0091 ± 0. 0039 min-1. Conclusions: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.

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