A freely accessible, adaptable hollow-fiber setup to reproduce first-order absorption: illustration with linezolid cerebrospinal fluid pharmacokinetic data

Abstract

The main objective of this study was to validate an algorithm and experimental setup to simulate first-order absorption pharmacokinetic profiles without altering the standard in vitro hollow fiber infection model (HFIM). For that, clinical cerebrospinal fluid (CSF) linezolid concentrations after 30-minute infusions at dosing regimens 600 mg q12 h, 900 mg q12 h, and 900 mg q8 h were reproduced in the HFIM over 4 days. To approximate the apparent first-order absorption observed on CSF pharmacokinetic profiles, we split the dosing interval into a series of sub-intervals during which continuous infusions were delivered to the system. During each sub-interval, the same amount of linezolid was delivered but the sub-intervals had different durations and flow rates which were computed by a newly developed algorithm. In addition, we independently reproduced plasma concentrations to validate our system. Samples were collected from the central reservoir and the extracapillary space (ECS) of the cartridge of the HFIM and assayed by liquid chromatography-tandem mass spectrometry. Observed pharmacokinetic parameters and concentrations in the ECS were compared with the target clinical pharmacokinetic parameters and concentrations. Observed pharmacokinetic parameters were within 20 % of target pharmacokinetic parameters for all experiments, thus validating the ability of our experimental setup to reproduce plasma and CSF linezolid pharmacokinetic profiles. The algorithm and setup are available in the open-source web application https://varacli.shinyapps.io/hollow_fiber_app/ to easily design other HFIM experiments.