Identifying a therapeutic target for ganciclovir against cytomegalovirus in immunocompromised children

Abstract

AIMS: Ganciclovir (GCV) is commonly used to treat cytomegalovirus (CMV) infections in immunocompromised children. Currently, the therapeutic target for effective treatment is unclear: Adult studies suggest that a serum area under the concentration-time curve (AUC(24h)) ≥40 mg/L·h correlates with effective CMV prevention. The aim of this study was to determine the serum GCV therapeutic target for the treatment of CMV viraemia in immunocompromised children. METHODS: Data from a multicenter retrospective audit of GCV dosing, therapeutic drug monitoring and plasma CMV viral loads in immunocompromised children were analysed using piecewise linear regression to determine viral dynamics during GCV treatment periods. A published population pharmacokinetic model from the same cohort was used to derive post hoc average daily AUC(24h). An E(max) model was developed in NONMEM to explore the effect of drug exposure on viral dynamics, adjusting for immune status. RESULTS: Fourteen children with 185 viral loads were included, encompassing 30 periods of viral load increases and 28 periods of decline. The estimated natural viral replication rate was 0.237 log(10) copies/mL/day (doubling time 1.3 days). White cell count (WCC) significantly affected the viral decline rate, with a maximum GCV-induced viral decline rate of 0.238 log(10) copies/mL/day. The GCV AUC(24h) corresponding to 90% maximal replication suppression and elimination effects were approximately 40 and 100 mg/L·h, respectively, when the WCC was 3.7 × 10(9)/L. CONCLUSIONS: A serum GCV AUC(24h) target of 40-100 mg/L·h may serve as a preliminary reference for the treatment of CMV infection in immunocompromised children. Notably, the therapeutic target is affected by the individual's immune status.