Klinik für Tumorbiologie an der Albert-Ludwigs Universität, Freiburg, Germany.
Eur J Cancer. 2010 Mar;46(5):920-5. doi: 10.1016/j.ejca.2009.12.028. Epub 2010 Jan 14.
To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine.
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.
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.
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.
确定口服 perifosine 的最大耐受剂量（MTD）和药代动力学。
接受固体肿瘤治疗的患者每周接受 100-800mg 的 perifosine 治疗。入选标准包括预期寿命>12 周，WHO 表现状态 2，血液、肝脏和肾脏功能正常，最近未接受过抗癌治疗。药物浓度采用 HPLC-MS/MS 进行分析。
共招募了 36 名患者（75%为男性，平均年龄为 54.7 岁，表现状态 1 占 72.2%）。不良反应包括恶心（69.4%）、腹泻（55.6%）、呕吐（52.8%）和腹痛（13.9%）。50%的患者使用了止吐药方案，包括糖皮质激素、多巴胺拮抗剂和 5-HT3 拮抗剂，作为治疗和/或预防措施。尽管每周 800mg 未达到 MTD，但由于腹泻和呕吐而停止治疗的两名患者可能与 perifosine 有关，这导致决定停止进一步的剂量递增。单次给药后的药代动力学特征为中位 t(max)=8.0-24.2h，中位 t(1/2)=81.0-115.9h，平均（几何）CL/f=0.28-0.43mL/min/kg。尿排泄率低于 1%。perifosine 略有蓄积，在 2-3 周后接近稳态。
在给予餐食和预防性止吐药的情况下，癌症患者口服 perifosine 的剂量可达 600mg/周，耐受性良好。基于其约 4 天的半衰期，每周一次的方案可能是合适的。
