Pharmacokinetics, Pharmacodynamics, and Therapeutic Drug Monitoring of Valganciclovir and Ganciclovir in Transplantation

Abstract

Ganciclovir and valganciclovir are first choice drugs for the prevention and treatment of cytomegalovirus infection and disease in solid organ and stem cell transplant recipients. Only a few studies on the pharmacokinetics and exposure/efficacy or exposure/safety relationships of ganciclovir and valganciclovir in transplant recipients have been published so far, and there are still controversies about the exposure parameter to use for therapeutic drug monitoring (TDM). We performed an extensive literature review of the clinical pharmacokinetics data, the exposure/effect relationships in terms of efficacy and safety, and the available tools for valganciclovir and ganciclovir TDM in adults and pediatrics transplant recipients. The pharmacokinetics of ganciclovir and valganciclovir is well described in adults and children, and a high interindividual variability is commonly observed. In contrast, the drug pharmacodynamics has been poorly described in adults and barely in children. The average 24‐hour area under the concentration‐time curve (AUC0–24h) seems to be the best predictor of efficacy and toxicity. The benefit of TDM remains controversial in adult patients but should be considered in children due to higher interindividual variability and lower probability of target attainment. Several bayesian estimators based on limited sampling strategies have been developed with this aim and may be used in clinical practice for the AUC‐based individual dose adjustment of ganciclovir and valganciclovir.

Pharmacokinetics of valganciclovir and voriconazole during prolonged intermittent renal replacement therapy in a lung transplant recipient

“…A limitation to our investigation is PK measurements were only taken during a single PIRRT session. We also acknowledge a strong association with efficacy and toxicity has not been found for ganciclovir PK parameters, and some have found stronger clinical associations with area under the curve 11 or intracellular ganciclovir triphosphate concentrations 12 than with trough plasma concentrations. If higher trough levels are targeted as might be preferred in the treatment of CMV infection, increased exposure could be achieved by dosing directly after PIRRT or by increased dose.…”

Subtherapeutic Exposure of Ganciclovir in Children Despite Appropriate Dosing: A Short Communication

“…Moreover, monitoring AUC 24 is recommended, as it has been reported to be a good indicator of efficacy and toxicity in pediatric patients. 23,24 This may be beneficial for individual treatment.…”

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients

“…Ganciclovir is another nucleoside analog of guanosine with antiviral activity against CMV and HSV. It is currently the recommended first-line option for the prevention and treatment of CMV infection and disease in solid organ transplant (SOT) and stem cell transplant recipients [ 31 , 32 , 33 , 34 ].…”

“…Given ganciclovir’s low oral bioavailability (~6%), the prodrug valganciclovir was developed for oral treatment with an improved oral bioavailability (~60%) [ 32 , 38 ]. The bioavailability of valganciclovir is 24–56% higher in the fed condition than that in the fasted condition.…”