Suzanne A.M. Wenker 1,5, Sergio Kamminga 2, Anders Åsberg 3, Aiko P.J. de Vries 4, Ann Vossen 2, J.G. Coen van Hasselt 1, Dirk Jan A.R. Moes 5, Anne-Grete Märtson 1
1 Leiden Academic Center for Drug Research, Leiden University (Leiden, Netherlands), 2 Medical Microbiology and Infection Control, Leiden University Medical Center (Leiden, Netherlands), 3 Department of Transplantation Medicine, Oslo University Hospital (Oslo, Norway), 4 Transplant Center, Leiden University Medical Center (Leiden, Netherlands), 5 Clinical Pharmacy and Toxicology, Leiden University Medical Center (Leiden, Netherlands)
Objectives
Cytomegalovirus (CMV) is a human herpesvirus that causes significant mortality and morbidity in immunocompromised patients (1). The first-line drug, ganciclovir, exhibits significant toxicity, which leads to treatment cessation and eventually failure. Furthermore, previous studies show that standard dosing of ganciclovir might not reduce viral load fast enough, suggesting the need for treatment optimization (2). Commonly, dosing schemes are based on pharmacokinetic/pharmacodynamic (PK/PD) targets. The most commonly used targets for (val)ganciclovir are AUC24hr > 50 μg*h/mL for prophylaxis and >80-120 μg*h/ml for treatment (3,4). Clinically, there have been patients identified where, under standard dosing regimens, therapeutic drug monitoring (TDM) has shown underexposure of ganciclovir, and unexplained treatment failure or resistance has occurred. The aims of the current study were to develop a population pharmacokinetic (pop-PK) model to investigate the ganciclovir target attainment and validate the model in four transplant recipients selected in a local hospital and a simulation population.
Methods
A previously published valganciclovir dataset with 155 patients was available for development of a population pharmacokinetic model using Monolix (2024R1, Lixoft, France) (5). The model was subsequently used to simulate (N=10000) PK profiles for varying dosing regimens for prophylaxis, as defined in the summary of product characteristics (SmPC), stratified by eGFR per dosing occasion (900 mg q24h for eGFR >60 mL/min/1.73 m², 450 mg q24h for eGFR 40-60 mL/min/1.73 m², 450 mg q48h for eGFR 25-40 mL/min/1.73 m², 450 mg twice weekly for eGFR<25 mL/min/1.73 m²) in Simulx (2024R1, Lixoft, France). Simulations were for 24 hours after reaching steady state (day 7). The percentage of target attainment of AUC0-24hr ≥50 μg*h/ml was calculated. Finally, four patients presented with CMV infection at a local hospital were analyzed for AUC0-24hr target attainment, and viral load decline was estimated over time.
Results
The final popPK model was a two-compartmental model with first-order oral absorption. Typical parameter values were 0.34 h-1(Ka), 16.44 L/h (Cl), 48.39 L (V1), 11.62 L/h(Q) and 56.7 L (V2). Bioavailability was fixed to 0.64 based on SmPC. Random effects for inter-individual variability were included for clearance (Cl) and volume of the central compartment (V1). The covariates weight and eGFR were added to Cl, and weight and sex to V1. A proportional residual error model was used. The relative standard error (RSE) of the population parameters were all below 20%. The percentage of target attainment of AUC24h >50 μg*h/ml for the simulated patient groups was 17%; 52%; 6.1%; 0%; 0% for eGFR >90; 60-90; 40-60; 25-40; <25 mL/min/1.73 m², respectively, for the standard recommended dosing schemes. Three patients showed low AUC0-24hr target attainment during the entire treatment period. One patient showed high target attainment, but only after doubling the dose, against common dose recommendations.
Conclusions
The results of our popPK model and the subsequent case series suggest that we may dose too low for (val)ganciclovir against CMV. The results of our simulation study demonstrated that for the standard recommended dosing schedule, a low target attainment is mostly seen in patients with low (<60) and high (>90) eGFR. This is highly clinically relevant as transplant recipients often have impaired kidney function or augmented renal function. Optimised ganciclovir dosing regimens need to be further evaluated in this patient population.
References:
1. Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol. 2021 Dec;19(12):759–73.
2. Märtson AG, Sturkenboom MGG, Knoester M, Van Der Werf TS, Alffenaar JWC, Hope W, et al. Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads. J Antimicrob Chemother. 2022 Feb 2;77(2):466–73.
3. Wiltshire H, Paya CV, Pescovitz MD, Humar A, Dominguez E, Washburn K, et al. Pharmacodynamics of Oral Ganciclovir and Valganciclovir in Solid Organ Transplant Recipients. Transplantation. 2005 Jun 15;79(11):1477–83.
4. McCreary EK, Narayanan N, Tängdén T, Märtson AG. (Val)ganciclovir dosing for cytomegalovirus: revisiting the 2005 Wiltshire et al. pharmacokinetic/pharmacodynamic target. CMI Commun. 2026 Mar;3(1):105171.
5. Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, et al. Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients: Clin Pharmacokinet. 2005;44(5):495–507.
Reference: PAGE 34 (2026) Abstr 12143 [www.page-meeting.org/?abstract=12143]
Poster: Drug/Disease Modelling - Infection