The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates

Leigh Marcus, Robert Murphy, Elizabeth Fox, Cynthia McCully, Raphael Cruz, Katherine E. Warren, Thorsten Meyer, Edward McNiff, Frank M. Balis, Brigitte C. Widemann

Research output: Contribution to journalArticle

Abstract

Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Methods: Satraplatin (120 mg/m 2) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC 0-48h : plasma UF AUC 0-48h. Results: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C max) 8.3 μM (5.7-10.6), area under the curve (AUC 0-48h) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t 1/2 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C max 0.07 μM (0.02-0.12), AUC 0-48h 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.

Original languageEnglish (US)
Pages (from-to)247-252
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

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Cerebrospinal fluid
Pharmacokinetics
Platinum
Intravenous Administration
Primates
Cerebrospinal Fluid
Plasmas
Area Under Curve
Cisplatin
Carboplatin
Refractory materials
Tumors
satraplatin
Atomic spectroscopy
Centrifugation
Dimethyl Sulfoxide
Absorption spectroscopy
Intravenous Infusions
Brain Neoplasms
Assays

Keywords

  • Non-human primate
  • Pharmacokinetics
  • Pharmocology
  • Satraplatin

ASJC Scopus subject areas

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

Cite this

The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates. / Marcus, Leigh; Murphy, Robert; Fox, Elizabeth; McCully, Cynthia; Cruz, Raphael; Warren, Katherine E.; Meyer, Thorsten; McNiff, Edward; Balis, Frank M.; Widemann, Brigitte C.

In: Cancer Chemotherapy and Pharmacology, Vol. 69, No. 1, 01.2012, p. 247-252.

Research output: Contribution to journalArticle

Marcus, L, Murphy, R, Fox, E, McCully, C, Cruz, R, Warren, KE, Meyer, T, McNiff, E, Balis, FM & Widemann, BC 2012, 'The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates', Cancer Chemotherapy and Pharmacology, vol. 69, no. 1, pp. 247-252. https://doi.org/10.1007/s00280-011-1659-z
Marcus, Leigh ; Murphy, Robert ; Fox, Elizabeth ; McCully, Cynthia ; Cruz, Raphael ; Warren, Katherine E. ; Meyer, Thorsten ; McNiff, Edward ; Balis, Frank M. ; Widemann, Brigitte C. / The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 69, No. 1. pp. 247-252.
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abstract = "Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6{\%}, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Methods: Satraplatin (120 mg/m 2) was administered as 1 h IV infusion in DMSO (5{\%}) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC 0-48h : plasma UF AUC 0-48h. Results: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C max) 8.3 μM (5.7-10.6), area under the curve (AUC 0-48h) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t 1/2 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C max 0.07 μM (0.02-0.12), AUC 0-48h 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3{\%} (2.2-7.4). Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.",
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T1 - The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates

AU - Marcus, Leigh

AU - Murphy, Robert

AU - Fox, Elizabeth

AU - McCully, Cynthia

AU - Cruz, Raphael

AU - Warren, Katherine E.

AU - Meyer, Thorsten

AU - McNiff, Edward

AU - Balis, Frank M.

AU - Widemann, Brigitte C.

PY - 2012/1

Y1 - 2012/1

N2 - Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Methods: Satraplatin (120 mg/m 2) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC 0-48h : plasma UF AUC 0-48h. Results: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C max) 8.3 μM (5.7-10.6), area under the curve (AUC 0-48h) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t 1/2 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C max 0.07 μM (0.02-0.12), AUC 0-48h 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.

AB - Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Methods: Satraplatin (120 mg/m 2) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC 0-48h : plasma UF AUC 0-48h. Results: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C max) 8.3 μM (5.7-10.6), area under the curve (AUC 0-48h) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t 1/2 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C max 0.07 μM (0.02-0.12), AUC 0-48h 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.

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KW - Pharmacokinetics

KW - Pharmocology

KW - Satraplatin

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