Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial

Abstract

Abstract Background Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown. Objectives To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI. Methods In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1–5; once daily on alternate days, Days 7–25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1. Results Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ± 1 and Day 25/26 were 0.0252 (0.0038–0.1220) mg/L and 0.0069 (0–0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142–0.3250) mg/L and 0.0206 (0–0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ± 1 were 272.5 (0–524) mg/kg and 280.5 (0–1120) mg/kg, respectively. Conclusions EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.