Anidulafungin exposure and population pharmacokinetics in critically ill patients with invasive candidiasis.

PURPOSE: Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients.

METHODS

Adult ICU patients receiving standard anidulafungin dosing [200 mg on day 1, then 100 mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5 mg×h/L).

RESULTS

Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period.

CONCLUSION

Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.