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IA15IL32
How inhaled nano-medicines can control PK response
Satomi Onoue
University of Shizuoka, Japan
Pirfenidone (PFD) is clinically used for treatment of idiopathic pulmonary fibrosis; however, previous clinical studies demonstrated that orally-taken PFD often caused phototoxic skin responses (51.4% of patients) and severe gastrointestinal (GI) dysfunctions (49.1%). Dry powder inhalation system of PFD might be efficacious for controlling distribution of PFDin skin and GI, possibly leading to reduced systemic side-effects.
The present study aimed to develop novel respirable powder formulation of PFD (PFD-RP) for minimizing systemic exposure of PFD and maximizing topical effects in pulmonary tissues. To clarify the phototoxic potential, photobiochemical properties of PFD were examined with focus on UV absorption, generation of reactive oxygen species (ROS), lipid peroxidation, and DNA impairment. In vivo phototoxicity testing was conducted after oral administration of PFD (30–160 mg/kg). PFD-RP was prepared with a jet-mill, and physicochemical properties were characterized in terms of appearance, particle size distribution, and in vitro inhalation performance. In vivo pharmacological effects of PFD-RP were also assessed in experimental rat asthma/COPD models. Pharmacokinetic and safety studies on PFD formulations were carried out after oral and intratracheal administrations. PFD exhibited intense UVA/B absorption with molar extinction coefficient of 1,290 M-1･cm-1 and generated ROS, including singlet oxygen and superoxide, after exposure to simulated sunlight (Xe lamp, 250 W/m2). These photochemical data suggested the potent photoreactivity of PFD, which might be key trigger for phototoxic reactions. Based on the in vitro phototoxic assessments, PFD exhibited potent photoirritant risk, although in vitro photogenotoxic reaction of pirfenidone was negligible. Photostability testing demonstrated that PFD-RP, as well as PFD powder, weremarkedlymore photostable than PFD solution. Laser diffraction and cascade impactor analysis of newly developed PFD-RP, consisting of jet-milled PFD and lactose carriers, suggested its high dispersion and in vitro inhalation performance. Inhaled PFD-RP (0.3 mg-PFD/rat) could suppress antigen-evoked inflammatory events in experimental asthma/COPD model rats as evidenced by reduced infiltration of inflammatory cells and decrease of inflammation-related biomarkers in the pulmonary tissues. The PFD-RP at a pharmacologically effective dose could also reduce phototoxic skin responses and GI dysfunctions of PFD because of its lower systemic exposure than that after oral administration of PFD at the phototoxic dose (160 mg/kg). From these findings, the PFD-based inhalation therapy would be an attractive alternative to current oral therapy of PFD with a better safety margin for clinical treatment of idiopathic pulmonary fibrosis.
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