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European Journal of Clinical Pharmacology

, Volume 74, Issue 11, pp 1449–1459 | Cite as

Population pharmacokinetics of fluconazole in liver transplantation: implications for target attainment for infections with Candida albicans and non-albicans spp.

  • Pier Giorgio Cojutti
  • Manuela Lugano
  • Elda Righi
  • Giorgio Della Rocca
  • Matteo Bassetti
  • William Hope
  • Federico Pea
Pharmacokinetics and Disposition

Abstract

Objectives

The study aims to assess the population pharmacokinetics of fluconazole and the adequacy of current dosages and breakpoints against Candida albicans and non-albicans spp. in liver transplant (LT) patients.

Patients and methods

Patients initiated i.v. fluconazole within 1 month from liver transplantation (LTx) for prevention or treatment of Candida spp. infections. Multiple assessments of trough and peak plasma concentrations of fluconazole were undertaken in each patient by means of therapeutic drug monitoring. Monte Carlo simulations were performed to define the probability of target attainment (PTA) with a loading dose (LD) of 400, 600, and 800 mg at day 1, 7, 14, and 28 from LTx, followed by a maintenance dose (MD) of 100, 200, and 300 mg daily of the pharmacokinetic/pharmacodynamic target of AUC24h/MIC ratio ≥ 55.2.

Results

Nineteen patients were recruited. A two-compartment model with first-order intravenous input and first-order elimination was developed. Patient’s age and time elapsed from LTx were the covariates included in the final model. At an MIC of 2 mg/L, a LD of 600 mg was required for optimal PTAs between days 1 and 20 from LTx, while 400 mg was sufficient from days 21 on. A MD of 200 mg was required for patients aged 40–49 years old, while a dose of 100 mg was sufficient for patients aged ≥ 50 years.

Conclusions

Fluconazole dosages of 100–200 mg daily may ensure optimal PTA against C. albicans, C. parapsilosis, and C. tropicalis. Higher dosages are required against C. glabrata. Estimated creatinine clearance is not a reliable predictor of fluconazole clearance in LT patients.

Keywords

Fluconazole Population pharmacokinetics Liver transplantation Personalized therapy Efficacy 

Notes

Acknowledgments

W. H. holds or has recently held research grants with F2G, AiCuris, Astellas Pharma, Spero Therapeutics, Matinas Biosciences, Antabio, Amplyx, Allecra, Auspherix, and Pfizer, and he holds awards from the National Institutes of Health, Medical Research Council, National Institute of Health Research, FDA, and the European Commission (FP7 and IMI). W. H. has received personal fees in his capacity as a consultant for F2G, Amplyx, Ausperix, Spero Therapeutics, Medicines Company, Gilead, and Basilea, and he is an Ordinary Council Member for the British Society of Antimicrobial Chemotherapy. M. B. has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Gilead, Menarini, MSD, Pfizer, The Medicines Company, Tetraphase, and Vifor. F. P. has received speaker honoraria from and attended advisory boards for Basilea Pharmaceutics, Gileads, MSD, and Pfizer.

Funding

This study was conducted as part of our routine work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2526_MOESM1_ESM.docx (246 kb)
ESM 1 (DOCX 246 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of UdineUdineItaly
  2. 2.Institute of Clinical PharmacologySanta Maria della Misericordia University Hospital of Udine, ASUIUDUdineItaly
  3. 3.Department of Anesthesia and Intensive Care MedicineSanta Maria della Misericordia University Hospital of Udine, ASUIUDUdineItaly
  4. 4.Infectious Diseases ClinicSanta Maria della Misericordia University Hospital of Udine, ASUIUDUdineItaly
  5. 5.Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK

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