Antibiotics (Sep 2023)

Dosing Optimization of Posaconazole in Lung-Transplant Recipients Based on Population Pharmacokinetic Model

  • Eliška Dvořáčková,
  • Martin Šíma,
  • Andrea Zajacová,
  • Kristýna Vyskočilová,
  • Tereza Kotowski,
  • Kateřina Dunovská,
  • Eva Klapková,
  • Jan Havlín,
  • Robert Lischke,
  • Ondřej Slanař

DOI
https://doi.org/10.3390/antibiotics12091399
Journal volume & issue
Vol. 12, no. 9
p. 1399

Abstract

Read online

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration–time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient’s age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

Keywords