A phase 1 pharmacokinetics study of deupirfenidone (LYT-100) in healthy older adults

Background Deupirfenidone, a selectively deuterated form of pirfenidone, is being developed for idiopathic pulmonary fibrosis (IPF), where tolerability limits current antifibrotic use. Deupirfenidone retains the biological activity of pirfenidone, and the differentiated pharmacokinetic (PK) profile may be associated with improved tolerability. Methods A phase 1, three-part, randomised, double-blind study was conducted to identify phase 2 doses. The safety, tolerability, steady-state PK and food effect profile of deupirfenidone were assessed in healthy older adults. Part 1 was a crossover study comparing deupirfenidone 850 mg twice daily to pirfenidone 801 mg three times daily. Part 2 was a crossover study comparing deupirfenidone 550 mg three times daily to pirfenidone 801 mg three times daily. Part 3 was a parallel study of deupirfenidone 550 mg three times daily titrated to deupirfenidone 824 mg three times daily versus placebo. Results Deupirfenidone 850 mg twice daily met the equivalence criterion to pirfenidone 801 mg three times daily for area-under-the-curve (AUC); however, maximum measured concentration ( C max ) and treatment-emergent adverse events (TEAEs) were higher with deupirfenidone. Deupirfenidone 550 mg three times daily met equivalence criterion to pirfenidone 801 mg three times daily for AUC; however, C max was lower. Frequency of gastrointestinal (GI) and nervous system (NS) TEAEs for deupirfenidone in the fed state was 40% lower than for pirfenidone. When deupirfenidone was titrated from 550 mg three times daily to 824 mg three times daily, PK parameters increased without increases in GI or NS TEAEs. Conclusions Results suggest evaluating a dose for deupirfenidone in healthy older adults of between 550 mg three times daily and 825 mg three times daily. Both doses are being evaluated in a 26-week, phase 2b study in patients with IPF.