Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension

Peposertib is an orally administered inhibitor of DNA-dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open-label, crossover three-period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film-coated tablets under fasted or fed conditions ("tablet fasted" or "tablet fed") or as an OS under fasted conditions ("OS fasted"), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed-to-fasted ratios were: area under the curve from time 0 to time t (AUC(0-t)), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC(0-infinity)), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (C-max) 104.47% (90% CI: 79.15, 137.90%). C-max was delayed under fed conditions (median time to maximum concentration [T-max] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS-to-tablet (fasted) ratios were: AUC(0-t), 124.83% (90% CI: 111.50%, 139.76%); AUC(0-infinity), 119.05% (90% CI: 104.47, 135.67%); and C-max 173.29% (90% CI: 135.78, 221.16%). Median T-max was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well-tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in C-max must be considered to optimize the chemo- or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings.