Boote D J, Dennis I F, Twentyman P R, Osborne R J, Laburte C, Hensel S, Smyth J F, Brampton M H, Bleehen N M
Medical Research Council Unit, Medical Research Council Centre, Cambridge, United Kingdom.
J Clin Oncol. 1996 Feb;14(2):610-8. doi: 10.1200/JCO.1996.14.2.610.
To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics.
Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion).
Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively.
PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.
确定在癌症患者中连续5天给予依托泊苷时联合输注PSC 833的最大耐受剂量（MTD）及毒性，并确定PSC 833对依托泊苷药代动力学的影响。
35例患者进入本研究，其中1例不符合入选标准。从第1天开始，依托泊苷以75至100mg/m²/d的剂量连续5天进行2小时输注。PSC 833从第2天开始给药，先给予2小时的负荷剂量，然后进行5天的持续输注。剂量从1至2mg/kg（负荷剂量）和1至15mg/kg/d（持续输注）逐步递增。
34例患者接受了53个周期的PSC 833与依托泊苷联合治疗。通过持续输注给予PSC 833剂量≥6.6mg/kg/d治疗的所有患者均达到了稳态血药浓度超过1000ng/mL。骨髓抑制是最常见的毒性反应。PSC 833主要的剂量相关毒性是可逆性高胆红素血症，在83%的周期中出现。PSC 833的剂量限制性毒性是严重共济失调，在接受12mg/kg/d治疗的9例患者中有2例出现，在接受13.5mg/kg/d和15mg/kg/d治疗的2例单独患者中也均出现。PSC 833浓度超过2000ng/mL导致依托泊苷曲线下面积（AUC）增加89%，依托泊苷清除率（Cl）降低45%，稳态分布容积（Vss）降低41%，α半衰期（t 1/2α）无显著增加，β半衰期（t 1/2β）显著增加19%和77%。
PSC 833可与依托泊苷联合给药，毒性可接受。该方案中PSC 833推荐的持续输注剂量为5天内10mg/kg/d。PSC 833导致依托泊苷暴露增加，接受PSC 833治疗的患者应减少依托泊苷剂量。
