Photodynamic therapy is an effective and often curative treatment for certain solid
tumors. The
porphyrin-based
photosensitizer Photofrin, the only Food and Drug Administration-approved
drug for this
therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous
phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl
pyropheophorbide-a (
HPPH), a
chlorin-type
photosensitizer with more favorable photophysical properties.
HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal
carcinoma, high-grade dysplasia associated with
Barrett's esophagus,
carcinoma of the lung, or multiple
basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted
HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous
phototoxicity responses were determined, as a function of time after
HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating
HPPH metabolites, and in vitro incubation of
HPPH with human liver microsomal preparations resulted in no metabolite or
glucuronic acid-
HPPH conjugate production. A minimal skin response to the solar simulator was observed, mostly in patients treated with the highest dose of
HPPH, 6 mg/m(2). All of the
HPPH pharmacokinetic parameters were consistent with a highly lipophilic agent that is concentrated in plasma and is nearly 100% bound to
plasma proteins; this was verified by
plasma protein binding studies. Whereas low concentrations of
HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general,
HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer
photodynamic therapy agent.