OBJECTIVE: The primary goal of this study was to evaluate the pharmacokinetics (PK) of ganciclovir (GCV) and its prodrug valganciclovir (VGCV) in a large cohort of lung transplant recipients. The secondary goal was to determine the probability of target attainment (PTA) for different pharmacokinetic/pharmacodynamic (PK/PD) targets. SUBJECTS AND METHODS: A population PK analysis was carried out using NONMEM version 7.4.0. In total, 379 GCV concentrations (194 and 185 concentrations sampled after VGCV and GCV administration, respectively) were obtained from 110 patients and were included in the analysis. Monte Carlo simulations were performed to assess PTA for (AUC24h) >50 mg·h/L and AUC24h of 80-120 mg·h/L. RESULTS: Estimated glomerular filtration rate (eGFR) was found to be the only significant covariate for GCV/VGCV clearance. Standard prophylactic and therapeutic GCV/VGCV dosing regimens lead to underdosing in patients with reduced eGFR values, particularly below 60 mL/min/1.73 m2 for VGCV and 70 mL/min/1.73 m2 for ganciclovir. For patients with higher eGFR levels, PTA levels are higher (21-35% in therapy and 44-50% in prophylaxis), but the PK show substantial variability, making individual dosing difficult. CONCLUSIONS: Standard prophylactic and therapeutic ganciclovir/VGCV dosing regimen leads to underexposure in patients with low eGFR but may be appropriate for patients with higher eGFR values. However, substantial variability in ganciclovir/VGC exposure makes it challenging to achieve efficacy targets in individuals. For this reason, therapeutic drug monitoring (TDM) should be considered. Our model can be integrated into TDM software and, alongside a TDM sample, be used for dosing guidance.

Certara Inc Princeton New Jersey USA

Department of Medical Chemistry and Clinical Biochemistry Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czechia

Division of Systems Pharmacology and Pharmacy Academic Centre for Drug Research Leiden University Leiden The Netherlands

Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Prague Lung Transplant Program 3rd Department of Surgery 1st Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czechia

Prague Lung Transplant Program Department of Pneumology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czechia

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