Intracellular Ganciclovir Triphosphate Concentrations in Children With Congenital Cytomegalovirus Infection.

BACKGROUND

Congenital cytomegalovirus (cCMV) infection is the most common cause of nonhereditary 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 (V)GCV 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 infants with cCMV to quantify GCV-TP and explore the kinetics of GCV-TP in this matrix.

METHODS

DBS samples were collected from infants with cCMV 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.

RESULTS

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 approximately 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.

CONCLUSIONS

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.