{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:29:30Z","timestamp":1785414570775,"version":"3.56.0"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Internal Grant Agency of the Tomas Bata Hospital and the Zlin Region","award":["25-2-011"],"award-info":[{"award-number":["25-2-011"]}]},{"award":["25-2-011"],"award-info":[{"award-number":["25-2-011"]}],"id":[{"id":"https:\/\/ror.org\/039fjjj43","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Health of the Czech Republic MH CZ-DRO-VFN64165 project"},{"name":"Charles University Cooperatio project"},{"id":[{"id":"https:\/\/ror.org\/024d6js02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Aim: This study aimed to develop a population pharmacokinetic (PK) model of intravenous fluconazole and, using model-based simulations, propose initial dosing recommendations that optimize efficacy while limiting toxicity. Methods: Therapeutic drug monitoring data from 116 adult patients (183 serum concentrations) treated with intravenous fluconazole between 2022 and 2025 at a single center were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were applied to identify dosing strategies that maximize the probability of achieving the PK\/PD efficacy target. Results: Estimated glomerular filtration rate (eGFR) was the strongest predictor of fluconazole clearance, and adjusted body weight (ABW) influenced the volume of distribution. For a patient with ABW of 75 kg and eGFR of 90 mL\/min, the estimated volume of distribution and clearance were 41.6 L and 0.81 L\/h, respectively. An eGFR-based dosing nomogram was developed, and simulations demonstrated that this approach outperformed standard dosing regimens in achieving the PK\/PD target. Conclusions: These findings suggest an initial loading dose (2.8 times the maintenance dose) followed by individualized, eGFR-guided maintenance dosing to enhance the safety and efficacy of intravenous fluconazole therapy; however, prospective clinical validation is required before routine clinical implementation.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080929","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population Pharmacokinetic Modeling of Intravenous Fluconazole to Inform eGFR-Based Dosing: A Simulation Study Demonstrating Superiority over Standard Regimens"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8491-2137","authenticated-orcid":false,"given":"Terezie","family":"Mackov\u00e1","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Tomas Bata Hospital Zlin, 762 75 Zlin, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3976-4007","authenticated-orcid":false,"given":"Martin","family":"Vodi\u010dka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Tomas Bata Hospital Zlin, 762 75 Zlin, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-7562","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Slana\u0159","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6541-738X","authenticated-orcid":false,"given":"Martin","family":"\u0160\u00edma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13054-015-0758-3","article-title":"Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study","volume":"19","author":"Sinnollareddy","year":"2015","journal-title":"Crit. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s00134-019-05599-w","article-title":"ESICM\/ESCMID task force on practical management of invasive candidiasis in critically ill patients","volume":"45","author":"Antonelli","year":"2019","journal-title":"Intensiv. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/civ933","article-title":"Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America","volume":"62","author":"Pappas","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e01554-20","DOI":"10.1128\/AAC.01554-20","article-title":"Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients","volume":"65","author":"Boonstra","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1186\/s13054-023-04742-w","article-title":"Pharmacokinetic and pharmacodynamic considerations for antifungal therapy optimisation in the treatment of intra-abdominal candidiasis","volume":"27","author":"Novy","year":"2023","journal-title":"Crit. Care"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ashley, C., Dunleavy, A., and Cunningham, J. (2019). The Renal Drug Handbook: The Ultimate Prescribing Guide for Renal Practitioners, CRC Press. [5th ed.].","DOI":"10.1201\/9780429460418"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s15010-017-1042-z","article-title":"Pharmacokinetics of antifungal drugs: Practical implications for optimized treatment of patients","volume":"45","author":"Bellmann","year":"2017","journal-title":"Infection"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s00134-020-06050-1","article-title":"Antimicrobial therapeutic drug monitoring in critically ill adult patients: A Position Paper#","volume":"46","author":"Alffenaar","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1016\/j.cmi.2020.05.037","article-title":"Antifungal therapeutic drug monitoring: Focus on drugs without a clear recommendation","volume":"26","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1002\/phar.2850","article-title":"Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists: Endorsed by the Mycoses Study Group Education and Research Consortium","volume":"43","author":"McCreary","year":"2023","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e01201-23","DOI":"10.1128\/aac.01201-23","article-title":"Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: An ASAP ECMO study","volume":"68","author":"Novy","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00991-24","DOI":"10.1128\/aac.00991-24","article-title":"Parametric and nonparametric population pharmacokinetic analysis of fluconazole in critically ill patients and dosing simulations for Candida infections","volume":"68","author":"Matusik","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e02019-20","DOI":"10.1128\/AAC.02019-20","article-title":"Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring","volume":"65","author":"Sandaradura","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00984-20","DOI":"10.1128\/AAC.00984-20","article-title":"Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time to Rethink Dosing","volume":"64","author":"Muilwijk","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1007\/s10096-021-04201-w","article-title":"Current fluconazole dosing regimens in critically ill adults result in under-exposure during early therapy","volume":"40","author":"Sandaradura","year":"2021","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Van Daele, R., Wauters, J., Lagrou, K., Denooz, R., Hayette, M.-P., Gijsen, M., Br\u00fcggemann, R.J., Debaveye, Y., and Spriet, I. (2021). Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients. Microorganisms, 9.","DOI":"10.3390\/microorganisms9102068"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New Creatinine- and Cystatin C\u2013Based Equations to Estimate GFR without Race","volume":"385","author":"Inker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154924","DOI":"10.1016\/j.jcrc.2024.154924","article-title":"Higher doses of fluconazole are needed to ensure target attainment in critically ill adults on continuous Veno-venous hemodialysis","volume":"85","author":"Coenradie","year":"2025","journal-title":"J. Crit. Care"},{"key":"ref_19","unstructured":"(2026, January 07). Rationale for EUCAST Clinical Breakpoints. Available online: https:\/\/www.eucast.org\/fileadmin\/src\/media\/PDFs\/EUCAST_files\/Rationale_documents\/Fluconazole_RD_v3.0_final_18_02.pdf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1128\/AAC.00424-11","article-title":"Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration: Using Monte Carlo Simulations To Predict Doses for Specified Pharmacodynamic Targets","volume":"55","author":"Patel","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1128\/AAC.00102-15","article-title":"Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation","volume":"59","author":"Watt","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa1114248","article-title":"Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C","volume":"367","author":"Inker","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1681\/ASN.2014121193","article-title":"Tubular Secretion in CKD","volume":"27","author":"Laha","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1158\/1078-0432.CCR-11-2503","article-title":"Proximal Tubular Secretion of Creatinine by Organic Cation Transporter OCT2 in Cancer Patients","volume":"18","author":"Ciarimboli","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1093\/infdis\/172.2.599","article-title":"Safety, Plasma Concentrations, and Efficacy of High-Dose Fluconazole in Invasive Mold Infections","volume":"172","author":"Anaissie","year":"1995","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1097\/00007691-200010000-00022","article-title":"Fluconazole-Induced Convulsions at Serum Trough Concentrations of Approximately 80 \u03bcg\/mL","volume":"22","author":"Matsumoto","year":"2000","journal-title":"Ther. 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