Population Pharmacokinetics and Bayesian Estimation of the Area Under the Concentration‐Time Curve for Ganciclovir in Adult Chinese Renal Allograft Recipients After Valganciclovir Administration

Abstract

Valganciclovir (VGCV) is the prodrug of ganciclovir (GCV). The objective of this study was to establish a population pharmacokinetic model (PPK) of GCV to investigate the PK characteristics of GCV after administration of VGCV in adult Chinese renal allograft recipients. Seventy Chinese renal allograft recipients were given 450 mg (n = 41) or 900 mg (n = 29) VGCV daily. Blood samples were drawn 0‐24 hours after 5 days’ therapy, and GCV plasma levels were determined. The PPK model was constructed using nonlinear mixed‐effects modeling, and the Bayesian estimation of AUC0‐24h was constructed for an individual patient based on limited plasma samples. The PK of GCV was best described by a 2‐compartment model with a first‐order absorption process. The CL/F, V2/F, Q/F, V3/F, Ka, and lag time of GCV were 15.8 ± 0.71 L/h, 10.9 ± 2.38 L, 3.98 ± 0.40 L/h, 167 ± 44.0 L, 0.23 ± 0.0078 1/h, and 0.93 ± 0.017 hours, respectively. Clearance of creatinine was found to have a significant impact on the CL/F of GCV (P < .01). Sampling strategies consisted of plasma concentrations 0 and 2 and 0, 2, and 4 hours after VGCV administration were shown to be suitable for the estimation of the GCV AUC0‐24h. The PPK model was acceptable and can describe the PK of GCV in Chinese renal transplant patients administered VGCV. The AUC0‐24h of GCV in Chinese renal transplant patients can be calculated by a limited sampling strategy method.

Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads

“… 33 reported in SOT recipients (K a of 0.13 h −1 ) and Chen et al . 34 reported in adult kidney transplant recipients (K a of 0.23 h −1 ). However, in other publications, higher K a values in SOT recipients have been reported—Perrotet et al .…”

Valganciclovir—Ganciclovir Use and Systematic Therapeutic Drug Monitoring. An Invitation to Antiviral Stewardship

“…Large inter-individual variability of serum levels was observed, and peak levels lower than 8.37 or greater than 11.86 mg/L and inadequate dosing, were related to poor outcome. Our data also set a basis to design a pharmacokinetic model in a higher group of patients with different serum drug determinations per patient needed to obtain more accurately the AUC and other PK/PD parameters for GCV exposure [ 41 ]. Further studies must be performed to confirm these results and to conclusively establish if VGCV/GCV TDM could be useful to improve outcomes and minimize drug-related toxicity and the emergence of CMV resistance in specific populations, like renal transplant and HSCT recipients [ 17 , 42 ].…”

Therapeutic Drug Monitoring of Ganciclovir: Where Are We?

“…54 Similarly, the mean ganciclovir clearance in renal transplant patients is lower (CL 0.6 L/h) 10 than that in other transplant recipients (CL mean 11.15 L/h). 10,52,53,55,[57][58][59]68,69 Apart from renal function, other factors may also affect ganciclovir elimination. Differences in drug regimens for specific transplantations (eg, immunosuppressives) may contribute to the variability in ganciclovir elimination.…”

“…9 Elimination of ganciclovir is biphasic, and both systemic and intercompartmental clearances have been estimated in various studies. 10,[52][53][54][55][56][57][58][59]67 In patients with mild renal impairment, ganciclovir clearance is almost half of the clearance value in healthy subjects (CL/F 14.9 L/h vs. 24.2 L/h). 54 Similarly, the mean ganciclovir clearance in renal transplant patients is lower (CL 0.6 L/h) 10 than that in other transplant recipients (CL mean 11.15 L/h).…”

“…54 Similarly, the mean ganciclovir clearance in renal transplant patients is lower (CL 0.6 L/h) 10 than that in other transplant recipients (CL mean 11.15 L/h). 10,52,53,55,57–59,68,69…”