Clinical pharmacokinetics of the PDT photosensitizers porfimer sodium (Photofrin), 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-induced protoporphyrin IX.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Bellnier
David A
DA
The Photodynamic Therapy Center & Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. david.bellnier@roswellpark.org
Greco
William R
WR
Loewen
Gregory M
GM
Nava
Hector
H
Oseroff
Allan R
AR
Dougherty
Thomas J
TJ
D000287:Administration, Topical; D000622:Aminolevulinic Acid / Q000032:analysis / Q000493:pharmacokinetics*; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D017323:Dihematoporphyrin Ether / Q000032:analysis / Q000493:pharmacokinetics*; D005470:Fluorometry; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy; D017319:Photosensitizing Agents / Q000032:analysis / Q000493:pharmacokinetics*
D017319:Photosensitizing Agents; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a; D000622:Aminolevulinic Acid; D017323:Dihematoporphyrin Ether