Hollow fiber system for TB: optimization studies with Moxifloxacin

Ramón García, Santiago
TUBERCULOSIS 2022 - EMBO Workshop on Tuberculosis 2022 - From innovation to intervention
Participation type: 
Other authors: 
D. Aguilar Ayala, M. Eveque, M.S. Rabodoarivelo, B. Octasari Susanto, N. Willand, U. Simonsson, S. Ramón García, A. Lucía
Paris, France. Sep 12-16 2022

The Hollow Fiber System for tuberculosis (HFS-TB) is an in vitro preclinical tool for drug evaluation. It can mimic pharmacokinetics (PK) profiles with high accuracy to forecast optimal dosing. Guidelines to assemble the system are public, but standard procedures, and reported fixed parameters to ensure reproducibility intra-laboratories are lacking. The objective of this study was to reveal the key parameters that guarantee the accuracy and reproducibility of PK and pharmacodynamics (PD) assays in HFS-TB. For this purpose, we used moxifloxacin (MXF).
For PK evaluation, we studied the suitability of the polysulfone cartridges by mimicking the concentration in human plasma from single oral dose of MXF (400 mg) in the absence of bacteria. Then, we mimicked MXF q.d. oral doses for three days with bacteria. All HFS-ports were sampled and drug quantification was performed by HPLC-MS/MS. Expected PK profiles were achieved in the central compartment but lower concentrations were found from the cartridge ports at Tmax. Traditionally, investigators have reported levels at the central compartment but not from cartridge ports where bacteria are exposed. Our study reveals that it cannot be assumed that drug concentrations at the central compartment will replicate inside the cartridges.
For PD evaluation, we tested three adaptation periods of M. tuberculosis H37Ra within cartridges: 24 h, 72 h, and 7 days before MXF administrations. We mimicked 400 mg q.d. oral dose as described above for nine days. Bacterial killing was dependent on the length of the adaptation period, being faster upon shorter adaptation times. This suggests the metabolic stage and initial bacterial load may influence kill rates and drug effectiveness interpretations. Bacterial killing was different than previous publications mimicking the same dose. Variability may rely on cartridge features, broth supplementation, inoculum size and adaptation period.
Our findings contribute to the standardization of the HFS-TB and should be considered when designing protocols to allow reproducibility between laboratories.
This work has received support from the Innovative Medicines Initiatives 2 Joint Undertaking (grant No 853989). This work reflects only the author's views, and the JU is not responsible for any use that may be made of the information it contains.