Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens

Abstract

Context: Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, in order to optimize dosing scheme.Method: All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using non-linear mixed-effect modelling. Monte Carlo simulations were used to optimize dosing regimen in order to maintain area under the concentration curve (AUC) in the preventive or therapeutic target.Results: Among the 105 children (374 concentration-time observations) included, 78 received intravenous (IV) ganciclovir, 19 oral valganciclovir and 6 both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and critically-ill children medical status were significantly associated with ganciclovir elimination.Conclusion: Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg/day oral or 15-20 mg/kg/day IV in children with normal eGFR and to 56 mg/kg/day oral or 20-25 mg/kg/day IV in children with augmented eGFR. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity

“…Resistances can appear within 10 days to 3 weeks from the initiation of antiviral therapy in patients with combined immunodeficiencies [ 25 ]. Some authors suggest that ganciclovir therapy might be optimized using therapeutic drug monitoring (TDM) especially in pediatric populations and in immunocompromised patients, as ganciclovir pharmacokinetic is highly variable and the optimal exposure for the treatment of CMV disease is unknown [ 26 , 27 ]. However, there is little information in this regard in children.…”

“…Nguyen et al recently characterized ganciclovir pharmacokinetics in patients younger than 18 years, suggesting increased doses to achieve a therapeutic exposure. However, these doses should be prospectively confirmed, and TDM could help to adjust them individually [ 27 ]. There is currently little evidence available regarding the use of combination therapy compared to the use of monotherapy for treating CMV infection in these patients.…”

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

“…Pharmacokinetic parameters were calculated using the population pharmacokinetic models of Nguyen et al 17 and MW/Pharm++ (Prague, Czech Republic). The corresponding AUC24 was calculated for each C min value.…”

“…10 Serum ganciclovir concentrations were collected during standard treatment and measured using a validated liquid chromatography with the tandem mass spectrometry LC-MS/MS method. 16 Pharmacokinetic parameters were calculated using the population pharmacokinetic models of Nguyen et al 17 and MW/Pharm++ (Prague, Czech Republic). The corresponding AUC24 was calculated for each C min value.…”

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

“…Overall, 10 studies developed population PK models of valganciclovir and/or ganciclovir in pediatric transplant recipients, including 5 encompassing several solid organ transplant types (kidney, liver, heart, lung, pancreas), 10,24,30–32 2 studies in kidney transplant recipients, 33,34 1 in heart transplant recipients, 35 and 1 study in SCT recipients (in addition to various solid organ transplant (SOT) transplant recipients) 36 . The last study did not specify the type of transplant 37 . Compared with adult studies, ganciclovir plasma PK was exclusively described using two–compartment models with first‐order absorption and first‐order elimination and mostly (9/10 studies) with a lag time to describe the hydrolyzation of valganciclovir into ganciclovir.…”