title: The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates.
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.
authors.affiliation: National Cancer Institute, Pediatric Oncology Branch, 10 Center Drive, Building 10-CRC, Room 1-5742, Bethesda, MD 20892-1101, USA. marculei@mail.nih.gov
authors.forename: Leigh
authors.initials: L
authors.lastname: Marcus
authors.forename: Robert
authors.initials: R
authors.lastname: Murphy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Cynthia
authors.initials: C
authors.lastname: McCully
authors.forename: Raphael
authors.initials: R
authors.lastname: Cruz
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.forename: Thorsten
authors.initials: T
authors.lastname: Meyer
authors.forename: Edward
authors.initials: E
authors.lastname: McNiff
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D019540:Area Under Curve; D016190:Carboplatin / Q000134:cerebrospinal fluid; D002945:Cisplatin / Q000134:cerebrospinal fluid; D006207:Half-Life; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D009944:Organoplatinum Compounds / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin; D016190:Carboplatin; D002945:Cisplatin