Bellnier David A, Greco William R, Loewen Gregory M, Nava Hector, Oseroff Allan R, Dougherty Thomas J
The Photodynamic Therapy Center & Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Lasers Surg Med. 2006 Jun;38(5):439-44. doi: 10.1002/lsm.20340.
Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor.
STUDY DESIGN/MATERIALS AND METHODS: Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor.
Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA.
We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted.
光动力疗法（PDT）利用在富氧环境中被光激活的光敏剂来破坏恶性肿瘤。罗斯韦尔帕克癌症研究所（RPCI）开展的PDT临床试验使用了光敏剂卟吩姆钠、叶绿素和5-氨基酮戊酸诱导的原卟啉IX（PpIX）。在一些研究中，测定了血液中以及偶尔在肿瘤组织中的光敏剂浓度。汇总并分析了这些个体研究的药代动力学（PK）数据。这是首次发表的直接比较卟吩姆钠和叶绿素PK的综述。
研究设计/材料与方法：从在RPCI接受PDT治疗的患者身上获取血液和组织样本。使用荧光分析法测定卟吩姆钠、叶绿素和PpIX的浓度。采用非线性混合效应建模方法分析叶绿素的PK数据（输注后长达4天；二室模型），并采用一种更简单的多患者数据汇总方法对卟吩姆钠和叶绿素的PK数据进行建模（输注后至少150天；三室模型）。将生理参数标准化以对应标准（70千克；体表面积1.818平方米）男性，以便于比较卟吩姆钠和叶绿素。
卟吩姆钠和叶绿素的血清浓度-时间曲线显示出较长的循环半衰期，静脉输注后3个月以上仍可检测到这两种光敏剂；然而，估计的血浆清除率（标准人）卟吩姆钠（25.8毫升/小时）明显低于叶绿素（84.2毫升/小时）。卟吩姆钠和叶绿素中央室的分布容积（标准人）分别约为血浆容积大小（分别为3.14升和4.29升），这意味着两种光敏剂几乎100%与血清成分结合。局部应用5-氨基酮戊酸后几天内，PpIX的循环水平通常相当低，降至仪器灵敏度水平以下。
我们对叶绿素和卟吩姆钠的PK进行了建模。PK参数估计可能部分解释了卟吩姆钠而非叶绿素导致的相对较长的皮肤光敏性。鉴于光动力疗法领域潜在的影响以及有限的实验PK数据开展肿瘤和正常组织中光敏剂动力学的进一步临床研究是必要的。
