TY - JOUR
T1 - Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients
AU - Ahmed, Tamer A.
AU - Hayslip, John
AU - Leggas, Markos
PY - 2013/12
Y1 - 2013/12
N2 - 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 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. 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.
AB - 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 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. 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.
KW - High-dose
KW - Leukemia
KW - Pharmacokinetics
KW - Simvastatin
UR - http://www.scopus.com/inward/record.url?scp=84890431722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890431722&partnerID=8YFLogxK
U2 - 10.1007/s00280-013-2326-3
DO - 10.1007/s00280-013-2326-3
M3 - Article
C2 - 24162379
AN - SCOPUS:84890431722
SN - 0344-5704
VL - 72
SP - 1369
EP - 1374
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -
