In vivo pharmacokinetic and pharmacodynamic study of inhalable pirfenidone microparticles prepared via high-energy bead milling

Purpose: Pirfenidone (PRF) is the first FDA-approved active pharmaceutical ingredient for the treatment of idiopathic pulmonary fibrosis (IPF). However, it has severe adverse effects such as photophobia and gastrointestinal disorder. Administration of PRF through the pulmonary route requires a relatively low effective dose and has few adverse effects. We evaluated the efficacy of inhalable PRF microparticles, which we manufactured via wet bead milling, to examine their bioavailability and efficacy when delivered through the pulmonary route as dry powder inhaler. Methods: Bead milled microparticles of PRF were prepared using high-energy dry or wet bead milling. Bioavailability of PRF was confirmed via in vivo pharmacokinetic (PK) experiments; in vivo pharmacodynamic experiments were performed using a bleomycin induced IPF rat model. Results: Wet bead milling was more efficient than dry bead milling owing to the high crystallinity and cohesiveness of PRF. Furthermore, in vivo PK experiments demonstrated that administering PRF via the pulmonary route was more than twice as effective as the oral route. Similarly, the therapeutic impact of PRF delivered via the pulmonary route was more optimized than that of PRF delivered via the oral route. Conclusion: These findings indicate that the bioavailability, distribution in the lungs, and therapeutic effect of PRF are superior when administered via the pulmonary route compared to the oral route.