单-L-天冬氨酰氯代二氢卟吩e6（NPe6）光动力疗法在成年原发性或继发性皮肤及黏膜表面癌症患者中的药代动力学及临床效果

Pharmacokinetics and clinical effects of mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients with primary or secondary cancer of the skin and mucosal surfaces.

作者信息

Chan Andrew L, Juarez Maya, Allen Roblee, Volz William, Albertson Timothy

机构信息

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, CA, USA.

出版信息

Photodermatol Photoimmunol Photomed. 2005 Apr;21(2):72-8. doi: 10.1111/j.1600-0781.2005.00138.x.

DOI:10.1111/j.1600-0781.2005.00138.x

PMID:15752124

Abstract

BACKGROUND/PURPOSE: Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT).

METHODS

This open label phase I clinical trial at the University of California, Davis Medical Center examined the pharmacokinetic properties of Npe6 and clinical response to PDT with this photosensitizer. A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (basal cell carcinoma = 22 lesions, squamous cell cancer = 13 lesions, papillary carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1)) 4-8 h prior to light activation. The total light dose (range 25-200 J/cm2) depended on the tumor shape and size. Light was delivered using an argon-pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed.

RESULTS

Four weeks post-PDT, 20 of 22 basal cell carcinoma tumors (91%) showed a complete response. Eighteen of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56%) or partial (n = 3/27, 11%) response. Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration. Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11 individual patients indicated that a two-compartment model with a residual phase best fits the data. The mean alpha, beta, and terminal half-lives were 8.63+/-2.92, 105.90+/-37.59 and 168.11+/-53.40 h (+/-1 SD), respectively. The observed mean volume of distribution was 5.94+/-2.55 l, and the mean clearance was 0.0394+/-0.0132 l/h. These values were independent of the dose administered.

CONCLUSION

The photosensitizer, NPe6, was well tolerated with minimal phototoxic side effects, and demonstrated preliminary efficacy against cutaneous malignancies.

摘要

背景/目的：单-L-天冬酰胺基二氢卟吩e6（NPe6）是一种具有化学纯度、在664nm波长处有吸收且可能用于光动力疗法（PDT）的光敏剂。

方法

在加利福尼亚大学戴维斯医学中心进行的这项开放标签I期临床试验，研究了Npe6的药代动力学特性以及该光敏剂光动力疗法的临床反应。14例患有浅表恶性肿瘤的癌症患者（基底细胞癌=22个病灶，鳞状细胞癌=13个病灶，乳头状癌=14个病灶）接受了单次静脉注射Npe6。患者在光激活前4 - 8小时接受五个递增剂量之一（0.5mg/kg（n = 4）、1.0mg/kg（n = 3）、1.65mg/kg（n = 3）、2.5mg/kg（n = 3）或3.5mg/kg（n = 1））。总光剂量（范围25 - 200J/cm²）取决于肿瘤的形状和大小。使用氩泵浦可调谐染料激光进行光照。在28天内测量血清NPe6浓度。观察NPe6的毒性和皮肤临床疗效。

结果

光动力疗法后四周，22个基底细胞癌肿瘤中的20个（91%）显示完全缓解。27个其他恶性皮肤肿瘤中的18个显示完全缓解（n = 15/27，56%）或部分缓解（n = 3/27，11%）。在Npe6剂量水平为1.65mg/kg或更高时，未缓解者较少。14例患者中只有2例经历了肯定与NPe6给药相关的不良事件。14例患者中有12例在NPe6给药后1周内光敏反应消退。对11例个体患者血清水平的分析表明，具有残留相的二室模型最符合数据。平均α、β和终末半衰期分别为8.63±2.92、105.90±37.59和168.11±53.40小时（±1标准差）。观察到的平均分布容积为5.94±2.55升，平均清除率为0.0394±0.0132升/小时。这些值与给药剂量无关。