Target attainment of valganciclovir prophylaxis against cytomegalovirus

6 Background: Cytomegalovirus (CMV) is a human herpesvirus that causes significant mortality and morbidity in immunocompromised patients. Previous studies show that standard dosing of valganciclovir, the first-line drug, might not sufficiently reduce viral load, indicating the need for treatment optimisation. Factors such as a high interpatient variability in pharmacokinetics, comedications and frequently impaired kidney function may lead to suboptimal drug concentrations with standard dosing regimens, leading to increased treatment failure, toxicity and resistance. Therefore, therapeutic drug monitoring (TDM) is occasionally considered. To perform TDM and optimize drug regimens, defining a pharmacokinetic (PK) /pharmacodynamic (PD) target is essential. For valganciclovir prophylaxi,s a PK target of AUC 40–50 μg*h/mL is often used. The aim of this study was to investigate the target attainment of current standard valganciclovir dosing in solid organ transplant patients. Materials and methods: In this study, a dataset of 157 adult kidney, liver or heart transplant recipients was used to develop a population PK model using Monolix (Lixoft). The dataset included information on drug dosing, age, weight, serum creatinine, type of solid organ transplant (kidney, liver, heart) and sex. eGFR was calculated using CKD-EPI. The population PK model was used to simulate (N = 1000) PK profiles for varying dosing regimens, defined by the manufacturer and stratified on eGFR (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 (Lixoft). Simulations were conducted for over a week period, with AUC(0 – 24 h) values calculated. Target attainment of AUC ≥ 40 and ≥50 μg*h/ml over 24 h was calculated. Results: The final population PK model was a two-compartmental model with first-order absorption. Random effects 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. AUC ≥ 40 μg*h/ml (24 h) attainment was 47%, 81%, 25%, 2.9% and 0% for eGFR >90, 60–90, 40–60, 25–40 and <25 mL/min/1.73 m2, respectively. AUC > 50 μg*h/mL (24 h) attainment was 17%; 52%; 6.1%; 0%; 0% for eGFR >90; 60–90; 40–60; 25–40; <25 mL/min/1.73 m2 respectively. Conclusions: Current valganciclovir dosing recommendations show poor target attainment particularly at eGFRs <60 and >90 mL/min/1.73 m2. The results of this study indicate that current dosing adjustment based on eGFR might lead to low AUC24hr of valganciclovir which may increase the risk of treatment failure due to subtherapeutic exposure. Furthermore, other studies defining a PK/PD target for valganciclovir are scarce and it remains unclear if the AUC(24 h) ≥ 40–50 μg*h/mL target has been well defined. Therefore, there is a clear need for a large, multi-centre study combining both clinical and in vitro data to define a new PK/PD target and to optimize current dosing strategies, considering both exposure–response and exposure–toxicity relationships.