A Novel Hollow Fiber Infection Model (HFIM) for Antiviral PK/PD studies of CMV infection.

Abstract

The hollow fiber infection model (HFIM) is a translational in vitro model that links time-varying human pharmacokinetic profiles to the associated viral dynamic responses, from which pharmacokinetic/pharmacodynamic (PK/PD) targets can be derived. Establishing such targets is essential for antiviral dose selection and optimization. This is particularly important for cytomegalovirus (CMV) infection treatment, which primarily affects vulnerable patient populations. PK/PD targets for ganciclovir, the first-line drug for treatment, are not yet defined. The lack of an undefined PK/PD target makes dose optimization challenging and may result in suboptimal exposure, prolonged toxicity, and the emergence of resistance. For the first time, we have demonstrated the use of a low-cost hemodialyzer hollow fiber cartridge with application for CMV infection using ganciclovir. We have established a system that 1) supports CMV culture for PD analysis, 2) reproduces a clinically relevant ganciclovir PK profile, and 3) maintains consistent drug exposure in the infected cells, allowing reliable PK/PD analysis. Quantitative methods such as tissue culture infectious dose 50% (TCID50) and quantitative PCR were used to assess both active virus replication and genome copies production. Ganciclovir PK was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This validation study serves as a fundamental step that can allow further PK/PD studies for ganciclovir and other antiviral agents that is still largely understudied. Consequently, this model could provide an affordable and practical platform for establishing clinically relevant PK/PD targets and guide treatment optimization.