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Extended-pulsed fidaxomicin regimen for treatment of Clostridioides (formerly Clostridium) difficile infection (CDI) maintained fidaxomicin stool concentrations above the C difficile minimum inhibitory concentration required to inhibit the growth of 90% of the bacteria (MIC90) until day 26±1 and there was no evidence of fidaxomicin accumulation in stool or plasma while systemic exposure to fidaxomicin and its major active metabolite, OP-1118, was low. This is according to data published in The Journal of Antimicrobial Chemotherapy investigating the pharmacokinetic profile of fidaxomicin in an extended-pulsed fidaxomicin regimen.
Investigators used data from the phase 3b/4 EXTEND trial in which patients aged ≥ 60 years with toxin-confirmed CDI were randomized to receive extended-pulsed fidaxomicin (oral fidaxomicin twice daily, days 1–5; once daily on alternate days, days 7–25). Plasma samples from 14 patients were included and stool from 12 of these was also provided. 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.
The median fidaxomicin plasma concentrations on day 5±1 and day 25/26 were 0.0252 mg/L (range, 0.0038–0.1220) and 0.0069 mg/L (range, 0–0.0887), respectively and those of OP-1118 were 0.0648 mg/L (range, 0.0142–0.3250) and 0.0206 mg/L (range, 0–0.3720), respectively. Median stool concentration of fidaxomicin on day 26 ± 1 were 272.5 mg/kg (range, 0–524) and were 280.5 mg/kg (range, 0–1120) for OP-1118. The investigators summated the findings by stating that using the extended-pulsed fidaxomicin regimen sustained median stool fidaxomicin concentrations well in excess of the fidaxomicin MIC90 until the end of treatment, despite the reduction in effective daily dose to one-quarter of that used in the standard 10 day regimen.
According to investigators, this work showed, “that the [extended-pulsed fidaxomicin] regimen led to minimal systemic exposure while providing high fidaxomicin and OP-1118 stool concentrations.” This supports the clinical efficacy findings that extended-pulsed fidaxomicin shows superior sustained clinical cure and reduced CDI recurrence compared with standard vancomycin therapy, in patients aged >60 years. They further report, “no evidence of fidaxomicin or OP-1118 accumulation in either plasma or stool, and fidaxomicin metabolism appeared unchanged by the extended dosing scheme.”
Reference
Guery B, Georgopali A, Karas A, et al. 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. J Antimicrob Chemother. 2020;75:1014-1018.
