Antimicrobial PK/PD – hollow fibre infection model (HFIM)

Simulate any time-concentration profile and sample over long periods

The hollow fibre infection model represents a cost effective pathway for faster development of safe and efficacious dosing regimens, both for existing under-exploited antibiotics, antibiotic combination therapies, and for new antibiotics as part of a regulatory submission process. EMA Workshop Non-Clinical Models to Identify PK/PD Indices and PD Targets In Vitro

The use of pre-sterilized 20ml FiberCell hollow fibre cartridge modules is widely reported for this application.

  • Precisely mimic any human concentration-time profile for your antimicrobial drug candidate or lead compound
  • Ideal for testing short half-life drug and combinations
  • Take multiple samples over time
  • Study the emergence of resistance over extended periods, months if necessary
  • Evaluate total kill
  • Co-cultivate different cell types, e.g. mammalian cells, bacteria, viruses
  • Rank new antimicrobial compounds by first testing a range of half-lives/exposure times in vitro

Hollow Fibre 2-compartment PK/PD system

Cross section through hollow fibre cartridge

How does it work?

Nutrient broth with test drugs is rapidly circulated through the porous-walled hollow fibres (3 fibres only are shown here for simplicity) using the Duet Pump to generate flow rates of >=60ml per minute. Drug concentrations equilibrate throughout the complete loop including reservoir, extracapillary “PD compartment”, and the luminal “PK compartment”.  Drug exposure of the cells in the extracapillary compartment is precisely controlled by diluent addition and waste removal as with the classic chemostat single compartment model.

Chemostat compared to hollow fiber

 

Endorsed by the EMA for PK/PD studies with Mtb.

“The Agency has published on 7 February 2015 a qualification opinion on the in-vitro hollow fiber system model of tuberculosis (TB) (EMA/CHMP/SAWP/47290/2015 Corr.).

[view extract]

Investigate the Emergence of Drug Resistance

The system is ideal for longer-term PK/PD studies to investigate the emergence of antimicrobial resistance, for example. It offers a level of precision and economy unattainable with animal models and bridges the gap between static assays, animal models and clinical trials

Essential reading :

The Hollow Fiber Infection Model, Principles and Practice by J.J. Cadwell [DOWNLOAD]

12 key advantages over
mouse thigh
model of infection

Single or 2-Drug Combination Systems

Test organisms are retained in the hollow fiber cartridge. Nutrient broth from the central reservoir is continuously re-circulated at a fast rate. Drug is added to the central reservoir and elimination kinetics are controlled by adding diluent to the central reservoir. The volume in the central reservoir remains constant. Combinations of  antibiotics can be tested using automatic syringes. Fibercell cartridges, DUET pump, 5-port central reservoir and 2-port diluent waste reservoir caps are available from KDBIO, see : Products for HFIM

HFIM set-up for antibiotic pk/pd

Click image to enlarge

Multiple pump set-up (2 experiments per pump)

Example hollow fibre infection model installation

Example laboratory set up for the hollow fibre infection model (4 pumps 8 cartridges)

  • Diluent and waste reservoirs are kept outside the incubator.
  • FiberCell Duet Pumps maintain high constant flow rates keeping the concentration in the central reservoir equilibrated with that of the extra-capillary space.
  • Low flow rate micro-processor controlled peristaltic pumps add and remove diluent from the central reservoir inside the incubator.
  • Sampling via the side ports on the hollow fiber cartridge.

Biosafety for drug resistant pathogenic or genetically modified agents

FiberCell® hollow fibre cartridges are fully disposable and provide biosafe containment for testing of drug resistant or genetically modified organisms.

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