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Understanding the PK/PD Relationship: The Hollow Fibre Infection Model

The Covid-19 pandemic is a stark reminder that infectious diseases and their sometimes devastating effects will always have to be reckoned with. However, beyond Covid-19 a second global health crisis is emerging, and it is imperative that we act now to prepare for the increasing development of antimicrobial resistance (AMR) towards our currently existing arsenal of antibiotics.

The key to de-risking and expediting the development and approval of new antimicrobials is a detailed understanding of the relationship between the fate of the antimicrobial compound in the body: pharmacokinetics (PK), and the impact of exposure to the compound on the target microbe: pharmacodynamics (PD). This understanding is essential for development of optimal human dosing regimens, maximising efficacy and minimising the emergence of resistance. Only with this understanding will we mitigate the risk of clinical trial failure, and ultimately extending the clinical utility of a new antimicrobial in the face of increasing AMR.

Among the several non-clinical in vivo and in vitro models of infection which provide complementary information to understand this PK/PD relationship, the in vitro Hollow Fibre Infection Model (HFIM) is the most versatile. Evotec’s comprehensive HFIM capabilities combined with its drug development expertise and unique EvostrAIn™ collection of microbial pathogens provide a versatile in vitro PK/PD platform to de-risk and accelerate the development of antibacterial, antifungal and antiviral compounds.

The Hollow Fibre Infection System consists of two principle compartments:

  1. a central reservoir and associated tubing, which constitutes a circulating system, and
  2. a hollow fibre cartridge consisting of thousands of hollow permeable capillaries, or fibres, housing the bacteria, fungi or virus of interest

The HFIM is a dynamic model that is able to simulate almost any given concentration-time profile for an antimicrobial compound or combination of compounds, without the constraints of animal PK. The containment of the bacterial in the peripheral compartment of the hollow fibre cartridge means the system is able to simulate PK profiles with no bacterial cell washout. It is also suitable for simulated dose range fractionation studies and can determine resistance prevention exposure for any simulated PK profile. Combining the ability to run long-duration experiments with multiple drug infusion profiles means that the HFIM is especially well suited to the development of antimicrobial combination therapy against slowly replicating bacteria such as Mycobacterium tuberculosis, a view which is supported by the European Medicines Agency (EMA).

When should the Hollow Fibre Infection Model be used in the drug discovery process?

  • Early screening of compounds can de-risk future HFIM experiments.
  • Studies at the pre-clinical stage (pre-IND) will help to improve understanding of the PK/PD relationship. This is particularly important if an animal model is not available, or if the animal can’t tolerate the inoculum levels that need to be tested for example in resistance studies.
  • During clinical development the HFIM can help to inform trial design. Hollow fibre studies can be performed based on human exposure data to address discrepancies between clinical and pre-clinical findings.
  • Even after drug approval the HFIM can be used to expand the label or optimise the dosing regimens.

Evotec has established HFIM capabilities in state-of-the-art containment level 2 facilities, with a growing team of dedicated Hollow Fibre specialists. Providing full microbiological support to projects and aided by specialist bioanalytical and mathematical modelling and simulation teams, Evotec can offer a bespoke in vitro PK/PD service tailored to advance individual antimicrobial development programmes.

Learn more about Evotec’s Hollow Fibre Infection Model by downloading our white paper

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