Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 6, pp 1369–1374

Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients

Short Communication

DOI: 10.1007/s00280-013-2326-3

Cite this article as:
Ahmed, T.A., Hayslip, J. & Leggas, M. Cancer Chemother Pharmacol (2013) 72: 1369. doi:10.1007/s00280-013-2326-3

Abstract

Purpose

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 Cmax) 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.

Conclusion

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.

Keywords

SimvastatinPharmacokineticsHigh-doseLeukemia

Supplementary material

280_2013_2326_MOESM1_ESM.tif (1.9 mb)
PBMCs concentration-time profile of simvastatin lactone following oral administration of MTD simvastatin in CLL patients. Simvastatin concentrations were normalized to the cellular volume of CLL cells in each PBMCs sample. SIM, simvastatin lactone. CLL cell volume = 200 fL. (TIFF 1979 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tamer A. Ahmed
    • 1
  • John Hayslip
    • 2
    • 3
  • Markos Leggas
    • 1
    • 2
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA
  2. 2.Markey Cancer CenterUniversity of KentuckyLexingtonUSA
  3. 3.Division of Hematology, OncologyUniversity of KentuckyLexingtonUSA