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

Eur J Cancer. 2010 Mar;46(5):920-5. doi: 10.1016/j.ejca.2009.12.028. Epub 2010 Jan 14.

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 status2, 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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Pain / chemically induced
  • Administration, Oral
  • Antiemetics / administration & dosage
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Diarrhea / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose*
  • Middle Aged
  • Nausea / chemically induced
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / adverse effects
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacokinetics
  • Treatment Outcome
  • Vomiting / chemically induced

Substances

  • Antiemetics
  • Antineoplastic Agents
  • Phosphorylcholine
  • perifosine