Malingré M M, Beijnen J H, Rosing H, Koopman F J, van Tellingen O, Duchin K, Ten Bokkel Huinink W W, Swart M, Lieverst J, Schellens J H
Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2001 Apr;47(4):347-54. doi: 10.1007/s002800000226.
To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination.
A total of 15 patients received during course 1 two doses of oral paclitaxel (2 x 60, 2 x 90, 2 x 120, or 2 x 160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion.
Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2 x 60 to 2 x 160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2 x 60, 90, 120, and 160 mg/m2 were 3.77 +/- 2.70, 4.57 +/- 2.43, 3.62 +/- 1.58, and 8.58 +/- 7.87 microM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95 +/- 3.94 microM.h.
Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2 x 90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.
研究每日两次口服紫杉醇联合环孢素A的剂量递增情况，以提高并延长紫杉醇的全身暴露量，探索该联合用药的最大耐受剂量和剂量限制性毒性（DLT）。
总共15例患者在第1疗程中接受两剂口服紫杉醇（2×60、2×90、2×120或2×160mg/m²），间隔7小时给药，并联合15mg/kg环孢素A，共同给药以增强紫杉醇的吸收。在随后的疗程中，患者每3周接受一次静脉注射紫杉醇，剂量为175mg/m²，输注3小时。
每日两次口服紫杉醇后的毒性一般较轻，包括紫杉醇给药常见的毒性以及轻度胃肠道毒性，如恶心、呕吐和腹泻，在较高剂量水平时更常发生。每日两次口服紫杉醇从2×60mg/m²递增至2×160mg/m²，并未使紫杉醇的血浆浓度-时间曲线下面积（AUC）显著增加。2×60、90、120和160mg/m²剂量后的AUC分别为3.77±2.70、4.57±2.43、3.62±1.58和8.58±7.87μM·h。静脉注射175mg/m²紫杉醇后的AUC为17.95±3.94μM·h。
紫杉醇剂量增加并未使药物的AUC值显著进一步增加。因此，每日两次给药方案的剂量递增未持续至DLT。由于每日两次给药与单剂量给药相比似乎导致更高的AUC值（我们之前已发表的数据），我们建议在未来研究中采用每日两次口服紫杉醇给药。尽管由于每个剂量水平的患者数量有限以及患者间差异较大，药代动力学数据难以解释，但我们建议对2×90mg/m²剂量水平进行进一步研究，因为该剂量水平显示出对紫杉醇的全身暴露量最高且安全性良好。
