title: Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study.
abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies.
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Yogesh T
authors.identifier: http://orcid.org/0000-0002-4629-6148
authors.initials: YT
authors.lastname: Patel
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Megan O
authors.initials: MO
authors.lastname: Jacus
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Abigail D
authors.initials: AD
authors.lastname: Davis
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: David C
authors.initials: DC
authors.lastname: Turner
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Vuppala
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.).
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: Departments of Pharmaceutical Sciences (Y.T.P., M.O.J., A.D.D., D.C.T. C.F.S.), Hematology (N.B.), and Developmental Neurobiology (R.J.G.), Preclinical Pharmacokinetic Shared Resource (P.K.V., B.B.F.), St. Jude Children's Research Hospital, Memphis, Tennessee; Merck, Rahway, New Jersey (D.C.T.); and Cambridge Cancer Centre, Cambridge, United Kingdom (R.J.G.) clinton.stewart@stjude.org.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003603:Cytotoxins / Q000008:administration & dosage* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D017551:Microdialysis / Q000379:methods*; D019821:Simvastatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D003603:Cytotoxins; C532833:simvastatin hydroxyacid; D019821:Simvastatin