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Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model

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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.

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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.

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Correspondence to Katherine E. Warren.

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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

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  • DOI: https://doi.org/10.1007/s00280-015-2711-1

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