I-098 Omar Elkayal

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

Omar Elkayal (1), Beatrijs Mertens (1,2), Ruth Van Daele (1,2), Katrien Lagrou (3,4), Joost Wauters (3,5), Isabel Spriet (1,2) †, Erwin Dreesen (1) †

(1) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – Leuven, Belgium. (2) Pharmacy Department, UZ Leuven – Leuven, Belgium. (3) Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium. (4) National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium. (5) Medical Intensive Care Unit, UZ Leuven – Leuven, Belgium. †Shared co-senior authorship

Introduction: Anidulafungin is an echinocandin, recommended as a first-line treatment of invasive Candida infections in critically ill patients (1). Pharmacokinetic (PK) variability in these patients may pose challenges to pharmacokinetic–pharmacodynamic (PKPD) target attainment (2). Recent evidence suggests that lower anidulafungin exposure may be anticipated in this population (3). Furthermore, there is growing evidence that patients with higher body weight are at increased risk for lower anidulafungin exposure due to PK alterations (4).

Objectives: The objectives of our work were

  • (i) to assess anidulafungin exposure and PKPD target attainment under standard dosing in critically ill patients,
  • (ii) to develop a population pharmacokinetics (popPK) model of anidulafungin in critically ill patients in the intensive care unit (ICU), and
  • (iii) to identify covariates with a clinically relevant impact on anidulafungin exposure.

Methods: Adult patients admitted to the ICU receiving standard anidulafungin dosing (200 mg intravenously [IV] on day 1, followed by 100 mg IV q24h from day 2) were included in the study. Rich blood sampling (7 samples per dosing interval) was performed on an early (day 2 ±1) and/or a late (day 5 ±1) treatment day (NCT04045366).

Using total anidulafungin plasma concentrations, a popPK model was developed. Different model structures were explored. Interindividual variability (IIV), inter-occasion variability (IOV; early versus late day), and residual unexplained variability (RUV) were quantified. A final model including covariate effects was built through two-way stepwise covariate modelling (αfwd=0.010, αbwd=0.001). The tested covariates included sex, baseline bodyweight and lean body mass, as well as time-varying sequential organ failure assessment (SOFA) score, serum albumin, serum creatinine, estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, aspartate aminotransferase, and alanine transaminase. A prediction-corrected visual predictive check was used to evaluate the final model.

Results: Twenty patients participated in the PK study (bodyweight range 50–134 kg and serum albumin range 20.2–39.1 g/L), contributing a total of 188 anidulafungin plasma concentrations (avg 8; range 3–17 per patient).

The popPK of anidulafungin was best described by a two-compartment model with linear elimination. For a typical 66-kg patient, the clearance (CL) was 0.98 L/h [6.7%] (typical value [relative standard error]), the intercompartmental clearance (Q) was 20.9 L/h [20.4%], the volume of distribution in the central compartment (Vc) was 5.85 L [23.1%], and the volume of distribution in the peripheral compartment (Vp) was 27.9 L [16.5%]. The IIV in CL, Vc, Vp was estimated at 35.4% coefficient of variation (CV), 223.4% CV and 54.7% CV, respectively. The RUV was described by a proportional error model (19.7% CV). Anidulafungin CL increased with bodyweight and Vc increased with lower levels of serum albumin.

PKPD target attainment in our population was 55% on day 1 and 60% on day 7. Monte Carlo simulations demonstrated that – under standard dosing – both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1, while bodyweight was the main driver of target attainment at day 7. The standard dosing regimen cannot reach 90% probability of target attainment on day 1 in any patient, and on day 7 only in patients with body weight below 55 kg, irrespective of serum albumin levels.

Conclusion: Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. Bodyweight and serum albumin should be considered for dosing in the ICU. Dose optimization opportunities should be assessed and validated in the future.

References:

  1. Pappas PG et al. 2016. Clin Infect Dis Off Publ Infect Dis Soc Am 62:e1–e50.
  2. Abdul-Aziz MH et al. 2020. Intensive Care Med 46:1127–1153.
  3. Liu X et al. 2020. J Clin Pharm Ther 45:1207–1217.
  4. Alsowaida YS et al. 2023. Am J Health Syst Pharm 80:503–517.
  5. Andes D et al. 2010. Antimicrob Agents Chemother 54:2497–2506.
  6. Anidulafungin_RD_v3.0_EUCAST.

Reference: PAGE 32 (2024) Abstr 10784 [www.page-meeting.org/?abstract=10784]

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