Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia

A collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study

E. S. Lowe, B. J. Kitchen, G. Erdmann, Linda Stork, B. C. Bostrom, R. Hutchinson, J. Holcenberg, G. H. Reaman, W. Woods, J. Franklin, B. C. Widemann, F. M. Balis, R. F. Murphy, P. C. Adamson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. Results: After oral TG (n = 35), the mean (± SD) peak plasma concentration was 0.46 ± 0.68 μM and the AUC ranged from 0.18 to 9.5 μM · h (mean 1.5 μM · h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 μM, respectively. The mean (± SD) TG clearance was 935 ± 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.

Original languageEnglish (US)
Pages (from-to)199-205
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume47
Issue number3
DOIs
StatePublished - 2001
Externally publishedYes

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Cerebrospinal fluid
Thioguanine
Pediatrics
Pharmacokinetics
Oncology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cerebrospinal Fluid
Plasmas
Neoplasms
Intravenous Infusions
6-Mercaptopurine
Maintenance
Nucleotides
Erythrocytes

Keywords

  • 6-Thioguanine
  • 8-OH-Thioguanine
  • Childhood
  • Leukemia
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia : A collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study. / Lowe, E. S.; Kitchen, B. J.; Erdmann, G.; Stork, Linda; Bostrom, B. C.; Hutchinson, R.; Holcenberg, J.; Reaman, G. H.; Woods, W.; Franklin, J.; Widemann, B. C.; Balis, F. M.; Murphy, R. F.; Adamson, P. C.

In: Cancer Chemotherapy and Pharmacology, Vol. 47, No. 3, 2001, p. 199-205.

Research output: Contribution to journalArticle

Lowe, ES, Kitchen, BJ, Erdmann, G, Stork, L, Bostrom, BC, Hutchinson, R, Holcenberg, J, Reaman, GH, Woods, W, Franklin, J, Widemann, BC, Balis, FM, Murphy, RF & Adamson, PC 2001, 'Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: A collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study', Cancer Chemotherapy and Pharmacology, vol. 47, no. 3, pp. 199-205. https://doi.org/10.1007/s002800000229
Lowe, E. S. ; Kitchen, B. J. ; Erdmann, G. ; Stork, Linda ; Bostrom, B. C. ; Hutchinson, R. ; Holcenberg, J. ; Reaman, G. H. ; Woods, W. ; Franklin, J. ; Widemann, B. C. ; Balis, F. M. ; Murphy, R. F. ; Adamson, P. C. / Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia : A collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study. In: Cancer Chemotherapy and Pharmacology. 2001 ; Vol. 47, No. 3. pp. 199-205.
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abstract = "Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. Results: After oral TG (n = 35), the mean (± SD) peak plasma concentration was 0.46 ± 0.68 μM and the AUC ranged from 0.18 to 9.5 μM · h (mean 1.5 μM · h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 μM, respectively. The mean (± SD) TG clearance was 935 ± 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.",
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TY - JOUR

T1 - Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia

T2 - A collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study

AU - Lowe, E. S.

AU - Kitchen, B. J.

AU - Erdmann, G.

AU - Stork, Linda

AU - Bostrom, B. C.

AU - Hutchinson, R.

AU - Holcenberg, J.

AU - Reaman, G. H.

AU - Woods, W.

AU - Franklin, J.

AU - Widemann, B. C.

AU - Balis, F. M.

AU - Murphy, R. F.

AU - Adamson, P. C.

PY - 2001

Y1 - 2001

N2 - Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. Results: After oral TG (n = 35), the mean (± SD) peak plasma concentration was 0.46 ± 0.68 μM and the AUC ranged from 0.18 to 9.5 μM · h (mean 1.5 μM · h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 μM, respectively. The mean (± SD) TG clearance was 935 ± 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.

AB - Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. Results: After oral TG (n = 35), the mean (± SD) peak plasma concentration was 0.46 ± 0.68 μM and the AUC ranged from 0.18 to 9.5 μM · h (mean 1.5 μM · h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 μM, respectively. The mean (± SD) TG clearance was 935 ± 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG.

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KW - 8-OH-Thioguanine

KW - Childhood

KW - Leukemia

KW - Pharmacokinetics

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