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Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes

Tenorio-Cañamás, Teresa, MD*,†; Grau, Santiago, PharmD, PhD‡,§; Luque, Sonia, PharmD, PhD‡,§; Fortún, Jesús, MD; Liaño, Fernando, MD, PhD; Roberts, Jason A., PharmD, PhD**,††

doi: 10.1097/FTD.0000000000000595
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Background: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO).

Methods: Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m2 surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV.

Results: Nine patients (55.6% male; age: 28–80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2–0.4) mg/L at low (predose) and 0.4 (<0.2–0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model.

Conclusions: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used.

*Department of Nephrology, Hospital Universitario Ramón y Cajal, Madrid;

Department of Medicine, School of Medicine, Universidad de Alcalá, Alcalá de Henares;

Pharmacy Department, Hospital del Mar, Infectious Pathology and Antimicrobial Research Group (IPAR), Institut Hospital del Mar d'Investigacions Médiques (IMIM), Universitat Autónoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona

§Spanish Network for Research in Infectious Diseases (REIPI RD 16/0016/0015), Instituto de Salud Carlos III, Madrid, Barcelona;

Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Madrid;

Department of Nephrology, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain;

**Faculty of Medicine, School of Pharmacy, the University of Queensland; and

††Departments of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Correspondence: Sonia Luque, PharmD, PhD, Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Passeig Marítim 25, 08003 Barcelona, Spain (e-mail: sluque@parcdesalutmar.cat).

This study was funded by a research grant from Astellas, Spain.

F. Liaño has received fundings from Astellas Pharma for developing research projects. S. Grau has received payment for lectures and speakers' bureaus from Pfizer, Novartis, and MSD. The remaining authors have no conflicts of interest to disclose.

The study protocol was approved by the local Ethical Committee of the institution (Date of approval July 6, 2013).

Written informed consents were obtained from all included patients or his/her legally authorized representatives.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received August 02, 2018

Accepted October 24, 2018

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