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

Diane E. Cole, Cynthia M. Lester-McCully, Brigitte C. Widemann, Katherine E. Warren

Research output: Contribution to journalArticle

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 (Cmax) ranged from 11.7-19.3 μM, and remained >1 μM for >28 days. Time to Cmax (Tmax) was 19 h. The median (range) AUCPl was 3148 (2502-4705) μM/h, with a median (range) terminal half-life (t1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (Tmax 64-235 h). CSF AUCs and t1/2 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.

Original languageEnglish (US)
Pages (from-to)923-928
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

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Cerebrospinal fluid
Pharmacokinetics
Primates
Cerebrospinal Fluid
Plasmas
Glioma
Tumors
Central Nervous System Neoplasms
Pediatrics
Critical Pathways
Chemotherapy
Neurology
Tandem Mass Spectrometry
perifosine
Macaca mulatta
Surgery
Area Under Curve
Mass spectrometry
Half-Life
Assays

Keywords

  • Glioma
  • Non-human primate
  • Perifosine
  • Pharmacokinetics
  • Pharmacology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology
  • Medicine(all)

Cite this

Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. / Cole, Diane E.; Lester-McCully, Cynthia M.; Widemann, Brigitte C.; Warren, Katherine E.

In: Cancer Chemotherapy and Pharmacology, Vol. 75, No. 5, 01.05.2015, p. 923-928.

Research output: Contribution to journalArticle

Cole, Diane E. ; Lester-McCully, Cynthia M. ; Widemann, Brigitte C. ; Warren, Katherine E. / Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 75, No. 5. pp. 923-928.
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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 (Cmax) ranged from 11.7-19.3 μM, and remained >1 μM for >28 days. Time to Cmax (Tmax) was 19 h. The median (range) AUCPl was 3148 (2502-4705) μM/h, with a median (range) terminal half-life (t1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (Tmax 64-235 h). CSF AUCs and t1/2 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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T1 - Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model

AU - Cole, Diane E.

AU - Lester-McCully, Cynthia M.

AU - Widemann, Brigitte C.

AU - Warren, Katherine E.

PY - 2015/5/1

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N2 - 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 (Cmax) ranged from 11.7-19.3 μM, and remained >1 μM for >28 days. Time to Cmax (Tmax) was 19 h. The median (range) AUCPl was 3148 (2502-4705) μM/h, with a median (range) terminal half-life (t1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (Tmax 64-235 h). CSF AUCs and t1/2 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.

AB - 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 (Cmax) ranged from 11.7-19.3 μM, and remained >1 μM for >28 days. Time to Cmax (Tmax) was 19 h. The median (range) AUCPl was 3148 (2502-4705) μM/h, with a median (range) terminal half-life (t1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (Tmax 64-235 h). CSF AUCs and t1/2 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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