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, have not yet been defined. The lack of defined targets 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 for CMV infection and ganciclovir treatment studies. We have established a system that i) supports CMV culture for PD analysis, ii) reproduces a clinically relevant ganciclovir PK profile, and iii) maintains consistent drug exposure in the infected cells, allowing reliable PK/PD analysis. Quantitative methods such as tissue culture infectious dose 50% (TCID 50 ) and quantitative PCR were used to assess both viral titer and viral genome 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 remain largely understudied. Consequently, this model could provide an affordable and practical platform for establishing clinically relevant PK/PD targets and guide treatment optimization.