2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, is employed in photodynamic therapy (PDT) for the treatment of various malignant lesions. PDT is a drug-device combined targeted treatment, and the clinical responses depend to a large extent on the photosensitizer distribution in target tissues and light exposure. In the present study, we aimed to give some suggestion for the development of HPPH-PDT from the perspective of photosensitizer biodistribution. For the first time, a PBPK model of HPPH was developed, which adequately described HPPH concentration-time profiles in rats plasma and various tissues. The rat PBPK model was further extrapolated to simulate the HPPH disposition in mouse and human. The simulated HPPH human serum concentrations yield a satisfactory agreement with observations at multiple dosing levels. It turned out that overweight may have a significant influence on HPPH exposure in human. Model simulated concentration-time profiles in human target tissues were also obtained. The appropriate time window to conduct light exposure for the treatment of digestive cancer and skin cancer could be 24-48 h and 48-96 h post-dose, respectively. Model simulations can explain the relevant clinical responses to some extent. The incorporation of the PBPK model into PDT could provide the photosensitizer concentrations not only in blood but also in target tissues, which may accelerate the development of this kind of treatment.
Keywords: HPPH; Human scale-up; Photodynamic therapy; Physiologically based pharmacokinetic model; Target tissues.
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