First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours

Abstract 

Aim

To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine.

Methods

Patients with solid tumours received perifosine at dosages ranging from 100–800mg/week. Eligibility criteria included life expectancy>12weeks, WHO performance status⩽2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC–MS/MS.

Results

Thirty six patients were recruited (75% males, mean age 54.7years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median t_max=8.0–24.2h, median t_1/2=81.0–115.9h and mean_geo CL/f=0.28–0.43mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2–3weeks.

Conclusion

Oral perifosine was tolerable up to 600mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4days, a weekly regimen may be appropriate.

Keywords: Perifosine, AEZS-104, D-21266, Oral medication, Akt inhibition, Phase I