Danica Michalickova1, Eliska Dvorackova1, Jakub Petrus2, Eva Klapkova2, Alzbeta Dutkova3, Tereza Kotowski3, Andrea Zajacova3, Elke H. J. Krekels4,5, Jan Havlin6, Robert Lischke4, Ondrej Slanar1
1Institute of Pharmacology, First Faculty of Medicine & General University Hospital, Charles University, Prague, Czech Republic, 2Department of Medical Chemistry and Clinical Biochemistry, Charles University, Second Faculty of Medicine and University Hospital Motol, 3Prague Lung Transplant Program, Department of Pneumology, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, 4Division of Systems Pharmacology and Pharmacy, Academic Centre for Drug Research, Leiden University, 5Certara Inc, 6Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University in Prague and Motol University Hospital
Introduction/objectives: Intravenous ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV) are gold standard treatments for both prevention and treatment of cytomegalovirus (CMV) infections (1). Our understanding of the pharmacokinetics (PK) of GCV/VGCV in lung transplant recipients remains limited (1-3). The primary goal of this study was to evaluate the PK of GCV/VGCV in a large cohort of lung transplant recipients. The secondary goal was to determine the probability of target attainment (PTA) for dosing protocols to achieve PK/PD targets for CMV prophylaxis and therapy. 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. eGFR and cotreatment with antimycotics were tested as covariates for clearance (CL), body weight was assessed as a covariate for CL and central volume of distribution (V1), while sex and cystic fibrosis diagnosis were tested as covariates for CL, V1 and bioavailability (F). For internal validation of the final model, bootstrap with 1000 resampled datasets and Normalized Prediction Distribution Error (NPDE) based on 1000 simulations were used. For Monte Carlo simulations (MCS), 1000 replicates of each patient from the original dataset were generated in Simulx Version 2024R1. Standard dosing regimens, in accordance with published GCV and VGCV dosing protocols (1), were simulated based on the final GCV/VGCV pop PK model, to obtain AUC24h at steady state for patients with different functional renal statuses. Probability of target attainment (PTA) was then calculated for AUC24h > 50 mg·h/L, and AUC24h between 80 and 120 mg·h/L. Results: Observed GCV plasma concentrations were best described by a two-compartment model with log-normally distributed interindividual variability (IIV) on CL, and V1. For F, a logit transformation was applied and a normal distribution for IIV was incorporated in the logit domain. eGFR was found to be the only significant covariate for CL of GCV/VGCV. For every 1 mL/min/1.73 m² decrease in eGFR, there was a 0.06 L/h decrease in GCV/VGCV CL. eGFR was 85.2 (16.8 – 153), median (min-max), mL/min/1.73 m² in this cohort of patients. Differences in PTA across groups with different eGFR highlight that recommended dosing may not be adequate for all patient populations. Specifically, PTA values for VGCV and GCV dosing for both prophylaxis and therapy of CMV, are very low for those with lower eGFR values, below 60 and 70 mL/min/1.73 m², respectively. A higher PTA of 27–44% is seen in patients with higher eGFR levels. Similarly, standard GCV dosing for CMV prophylaxis leads to PTA for patients with eGFR levels of 50–69 mL/min/1.73 m² and >70 mL/min/1.73 m² of 21% and 50%, respectively. For AUC24h of 80–120 mg·h/L, simulations indicate a PTA of approximately 21–35%, with a significant proportion of patients potentially receiving either suboptimal exposure (AUC24h <80 mg·h/L) or excessive exposure (AUC24h >120 mg·h/L). Due to the significant variability in GCV/VGCV PK, the recommended dosing regimens may not ensure optimal treatment for all lung-transplant recipients. A significant number of patients may be underexposed, potentially reducing clinical efficacy, or overexposed, which can increase the risk of toxic effects. Therefore, therapeutic drug monitoring (TDM) should still be considered to ensure safe and effective individual exposure. To improve TMD, the developed model can be integrated into TDM software to support monitoring of GCV/VGCV exposure in lung transplant patients. Conclusions: Standard prophylactic and therapeutic GCV/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 GCV/VGCV exposure makes it challenging to achieve efficacy targets in individuals. For this reason, TDM should be considered. Our model can be integrated into TDM software and, alongside a TDM sample, be used for dosing guidance.
1. Kotton CN and Kamar N. Infect Dis Ther. 2023;12(2): 333–342. 2. Vezina HE, et al. Br J Clin Pharmacol. 2014;78(2): 343–352. 3. Kiser TH, Fish DN, Zamora MR. J Heart Lung Transplant. 2012;31(2): 159–166.
Reference: PAGE 33 (2025) Abstr 11573 [www.page-meeting.org/?abstract=11573]
Poster: Clinical Applications