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

Abstract

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. Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64days. 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. Peak plasma concentrations (C max) ranged from 11.7-19.3µM, and remained >1µM for >28days. Time to C max (T max) was 19h. 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 4.1-10.1nM (T max 64-235h). 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 >35days. The mean CSF penetration was 0.16%. CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2months) after a single oral dose.