title: Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics of simvastatin at the maximum tolerated dose (MTD) of 7.5 mg/kg, twice daily, in the context of a pilot trial enrolling patients with recurrent and refractory chronic lymphocytic leukemia.
  
  
  METHODS
  Patients received simvastatin orally at MTD for 7 days during a 21-day cycle for 6 cycles. Blood samples were collected during cycle 1. Simvastatin lactone and carboxylate concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC-MS/MS assay.
  
  
  RESULTS
  Patients accrued to this study showed high variability in their exposure to simvastatin. Exposure was dose proportional (AUC and C max) as compared to those receiving standard hyperlipidemia therapy. Peak plasma concentrations ranged from 0.08 to 2.2 and from 0.03 to 0.6 μM for simvastatin lactone and carboxylate, respectively.
  
  
  CONCLUSIONS
  Our study shows that when simvastatin is administered at its MTD, only low micro-molar concentrations are achieved in plasma and PBMCs, which is consistent with the results observed in previous studies with lovastatin, but far lower than the concentrations required for anticancer effects in vitro. However, whether simvastatin at its MTD can confer therapeutic benefits to patients still remains to be determined.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Tamer A
authors.initials: TA
authors.lastname: Ahmed
authors.forename: John
authors.initials: J
authors.lastname: Hayslip
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020714:Maximum Tolerated Dose; D010865:Pilot Projects; D012008:Recurrence; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin