Abstract
Purpose
Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration.
Methods
Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration–time curves.
Results
Peak plasma concentrations (C max) ranged from 11.7–19.3 µM, and remained >1 µM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502–4705) µM/h, with a median (range) terminal half-life (t 1/2) of 193 (170–221) h. Plasma clearance was 494 (329–637) mL/h/kg. Peak CSF concentrations were 4.1–10.1 nM (T max 64–235 h). CSF AUCs and t 1/2 were 6358 (2266–7568) nM/h and 277 (146–350) h, respectively. Perifosine concentrations in the CSF remained over nM for >35 days. The mean CSF penetration was 0.16 %.
Conclusion
CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose.
Similar content being viewed by others
References
Momoto H, Nerio E, Holland E (2005) Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65(16):7429–7435
Pollack I, Hamilton R, Burger P, Brat D, Rosenblum M, Murdoch G et al (2010) Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the children’s oncology group. J Neurooncol 99:155–163
Mueller S, Phillips J, Onar-Thomas A, Romero E, Zheng S, Wiencke J et al (2012) PTEN promoter methylation and activation of the PI3 K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome. Neuro oncology 14(9):1146–1152
Kumar A, Fillmore H, Kadian R, Broaddus W, Tye G, Van Meter T (2009) The alkylphospholipid perifosine induces apoptosis and p21-mediated cell cycle arrest in medulloblastoma. Mol Cancer Res 7(11):1813–1821
Tokunaga E, Oki E, Egashira A, Sadanaga N, Morita M, Kakeji Y et al (2008) Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets 8:27–36
Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39
Sarkaria J, Galanis E, Wu W, Peller P, Giannini C, Brown P et al (2011) North Central cancer treatment group phase I trial N057 K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81(2):468–475
Kreisl T, Lassman A, Mischel P, Rosen N, Scher H, Teruya-Feldstein J et al (2009) A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol 92(1):99–105
Kondapaka S, Singh S, Dasmahapatra G, Sausville E, Roy K (2003) Perifosine, a novel alkylphospholipid with a 462 m.w., inhibits protein kinase B activation. Mol Cancer Ther 2:1093–1103
Konstantinov S, Topaska-Ancheva M, Benner A, Berger M (1998) Alkylphosphocholines: effects on human leukemia cell lines and normal bone marrow cells. Int J Cancer 77(5):778–786
Bagley R, Jurtzberg L, Rouleau C, Yao M, Teicher B (2011) Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells. Cancer Chemother Pharmacol 68(6):1537–1546
Gills J, Dennis P (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11:102–110
Schmidt-Heber M, Dadrowski R, Weimann A, Aicher B, Lohneis P, Busse A et al (2012) In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines. Investig New Drugs 30(2):480–489
Li Z, Tan F, Liewehr D, Steinberg S, Thiele C (2010) In vitro and in vivo inhibition of neuroblastoma tumor cell growth by Akt inhibitor perifosine. J Natl Cancer Inst 102(11):759–770
Hennessy B, Lu Y, Poradosu E, Yu Q, Yu S, Hall H et al (2007) Pharmacodynamic markers of perifosine activity. Clin Cancer Res 13(24):7421–7431
Crul M, Rosing H, de Klerk G et al (2002) Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 38:1615–1621
Van Ummersen I, Binger K, Volkman J et al (2004) A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 10:7450–7456
Unger C, Berdel W, Hanauske A, Sindermann H, Engel J, Mross K (2010) First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours. Eur J Cancer 46(5):920–925
de la Pena L, Burgan W, Carter D, Hollingshead M, Satyamitra M, Camphausen K et al (2006) Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells. Mol Cancer Ther 5(6):1504–1510
Becher O, Hambardzumyan D, Walker R, Helmy K, Nazarian J, Albrecht S et al (2010) Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res 70(6):2548–2557
McCully C, Balis F, Bacher J, Phillips J, Poplack D (1990) A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid. Lab Anim Sci 40(5):520–525
Institute for Laboratory Animal Research (2011) Guide for the care and use of laboratory animals, 8th edn. National Academy Press, Washington (DC)
Woo E, Messman R, Sausville E, Figg W (2001) Quantitative determination of perifosine, a novel alkylphosphocholine anticancer agent, in human plasma by reverse-phase liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl 759(2):247–257
Fox E, Bungay P, Bacher J et al (2002) Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey. JPET 301:1003–1011
Jacobs S, McCully C, Murphy R et al (2010) Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother Pharmacol 65:817–824
Acknowledgments
This work was presented in part at the 2012 International Society of Pediatric Neuro-Oncology Meeting in Toronto. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views herein do not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, or any other agency of the U.S. Government.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cole, D.E., Lester-McCully, C.M., Widemann, B.C. et al. Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. Cancer Chemother Pharmacol 75, 923–928 (2015). https://doi.org/10.1007/s00280-015-2711-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-015-2711-1