Intracellular Ganciclovir Tri-Phosphate Concentrations in Children with Congenital Cytomegalovirus Infection.

Abstract

Congenital cytomegalovirus (cCMV) infection is the most common cause of non-hereditary pediatric sensorineural hearing loss (SNHL). Importantly, cCMV is treatable, with the primary option being ganciclovir (GCV) or its orally bioavailable pro-drug valganciclovir (VGCV). A challenge for treating cCMV is the elevated risk for neutropenia associated with standard dosing. Optimizing and individualizing VGCV dosing could ameliorate the risk of neutropenia and improve efficacy but requires an understanding of the complex intracellular phosphorylation processes that govern the formation of the active GCV-triphosphate (GCV-TP) moiety. This study utilizes dried blood spot (DBS) samples from cCMV-infected infants to quantify GCV-TP and explore the kinetics of GCV-TP in this matrix. DBS samples were collected from infants with CMV infection receiving 16 mg/kg VGCV twice-daily as part of either a randomized, placebo-controlled clinical trial (ValEAR) or an open-label PK study. GCV-TP concentrations in DBS were determined using LC-MS/MS. Data indicate that GCV-TP is long-lived in DBS, with a half-life approximating 21 days. This leads to extensive GCV-TP accumulation in this matrix (primarily consisting of erythrocytes), with an expected ∼62-fold difference in first-dose and steady-state concentrations. Simulated data highlight the potential for DBS GCV-TP to be used as an objective adherence marker. These findings underscore the need to define the kinetics of GCV-TP in cell matrices relevant to its activity to determine appropriate VGCV dosing strategies in this population and establish safe and define effective therapeutic concentration targets.