Current development status of the second generation alkylphosphocholine analog perifosine

Alkylphosphocholines are a new class of antineoplastic agents interfering w ith membrane signal transduction pathways. The clinical development of oral administration of the lead compound hexadecylphosphocholine (miltefosine) in patients with solid tumors was prevented due to its dose-limiting gastro intestinal toxicity. The heterocyclic alkylphosphocholine derivative perifo sine is a promising candidate for clinical development, as revealed by an i mproved therapeutic index in animal experiments. Three phase I studies have been initiated to investigate the tolerability and pharmacokinetic propert ies of orally applied perifosine in patients with Various solid tumors. At present, preliminary data of the first phase I study using a weekly dose sc hedule are available. Up to now, a total of 32 patients were treated in a d ose range from 100-800 mg/week. Without antiemetic prophylaxis, vomiting oc curred as dose-limiting toxicity with 350 mg/week. Using an appropriate ant iemetic regimen, the dose could be escalated to the current 800 mg/week. Pa tient recruitment on this dose level is ongoing. No significant toxicities apart from gastrointestinal symptoms have been reported so far. Preliminary pharmacokinetic data indicate a dose-linearity of the maximum plasma conce ntration (C-max) and of the area under the concentration-time curve (AUC) o f perifosine. The terminal half-life ranges from 100-200 h. At present, the maximum tolerated dose of weekly applied perifosine has not yet been reach ed. Two further phase I trials have recently been initiated to investigate the tolerability of a daily dose schedule and of a different formulation Of perifosine. (C) 1998 Prous Science. Ail rights reserved.