膀胱内注射吉西他滨：一项1期药代动力学研究。

Intravesical gemcitabine: a phase 1 and pharmacokinetic study.

作者信息

Witjes J A, van der Heijden A G, Vriesema J L J, Peters G J, Laan A, Schalken J A

机构信息

Department of Urology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

出版信息

Eur Urol. 2004 Feb;45(2):182-6. doi: 10.1016/j.eururo.2003.09.014.

DOI:10.1016/j.eururo.2003.09.014

PMID:14734004

Abstract

INTRODUCTION

Superficial bladder cancer can be treated by transurethral resection and additional intravesical therapy. Although agents like Mitomycin C, Epirubicin and BCG are routinely used, there is a need for more potent and/or less toxic agents. Gemcitabine is a deoxycytidine analogue, used systemically for several tumours, such as non-localised bladder cancer, where it is effective and well tolerated. We investigated the use of three dose levels of gemcitabine when given intravesically in humans for safety and pharmacokinetic research.

MATERIAL AND METHODS

Patients with superficial bladder cancer, except pT1G3 or CIS were included. Six weekly instillations of 1000, 1500 or 2000 mg gemcitabine were given in 50 ml saline for one hour. Dose modifications were defined in case of dose limiting toxicities. Blood samples were taken before, and 5, 30, 60 (= evacuation) and 120 minutes after instillations 1, 3 and 6. Samples were used for blood counts and pharmacokinetics. Side effects were noted.

RESULTS

3, 4 and 3 patients were treated with 1000, 1500, and 2000 mg gemcitabine respectively, of which 2, 3 and 1 patients had highly recurrent tumours before treatment. Seven patients experienced side effects: 2 with dysuria after the first instillation, 2 after instillations 3-6 and 4-6 and in 3 patients headache, fatigue and heavy legs were experienced once. All side effects were reversible, non-limiting and WHO 1. No macroscopic hematuria was seen. Haematology showed only one case of drop in white blood cell count (lowest dose level, after the first instillation). Gemcitabine plasma levels were immeasurable or low, with peak levels between 30 and 60 minutes, decreasing after more instillations. The metabolite difluorodeoxyuridine reached levels of at most 5 microM, indicating a very low passage of the drug to the systemic circulation.

CONCLUSION

Intravesical gemcitabine in the dose used has minimal and reversible side effects. Plasma evaluation indicates that its intravesical use is safe.

摘要

引言

浅表性膀胱癌可通过经尿道切除术及额外的膀胱内灌注治疗。虽然丝裂霉素C、表柔比星和卡介苗等药物常规使用，但仍需要更有效和/或毒性更小的药物。吉西他滨是一种脱氧胞苷类似物，常用于多种肿瘤的全身治疗，如非局限性膀胱癌，在该疾病中它疗效显著且耐受性良好。我们研究了三种剂量水平的吉西他滨膀胱内给药在人体中的安全性和药代动力学。

材料与方法

纳入除pT1G3或原位癌（CIS）外的浅表性膀胱癌患者。将1000、1500或2000毫克吉西他滨溶于50毫升生理盐水中，每周灌注一次，共六次，持续一小时。如出现剂量限制性毒性则进行剂量调整。在第1、3和6次灌注前以及灌注后5、30、60分钟（=排空）和120分钟采集血样。样本用于血常规检查和药代动力学研究。记录副作用。

结果

分别有3、4和3例患者接受了1000、1500和2000毫克吉西他滨治疗，其中2、3和1例患者在治疗前有高度复发肿瘤。7例患者出现副作用：2例在首次灌注后出现排尿困难，2例在第3 - 6次和第4 - 6次灌注后出现排尿困难，3例患者分别有一次头痛、疲劳和下肢沉重感。所有副作用均可逆、无限制性且为世界卫生组织1级。未见肉眼血尿。血液学检查仅1例在首次灌注后出现白细胞计数下降（最低剂量水平）。吉西他滨血浆水平不可测或较低，峰值出现在30至60分钟之间，多次灌注后下降。代谢产物二氟脱氧尿苷水平最高达5微摩尔，表明该药物进入体循环的量非常低。