Science Pool

Evotec specializes in antifungal drug discovery with a focus on WHO and CDC priority human pathogens such as Aspergillus fumigatus, Candida spp, and Cryptococcus neoformans. Their track record in late-stage drug discovery is proven, aided by a range of established in vivo models of fungal infection that facilitate seamless progression from in vitro to in vivo studies.

Their expertise encompasses various areas, including in vitro compound characterization, invasive and localized in vivo fungal infection models, PK/PD mathematical modeling, and custom assay development tailored to individual project needs. They conduct comprehensive antifungal susceptibility testing to industry standards and offer specialized modalities such as combination testing to determine synergy or antagonism.

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Antimicrobial resistance (AMR) is one of the biggest health threats worldwide. Key to countering AMR is the development of novel anti-infective drugs. The limitations of animal models and clinical trial design have emphasised the importance of nonclinical pharmacokinetics/pharmacodynamics (PK/PD) platforms which provide a detailed understanding of the relationship between the fate of the antimicrobial compound in the body (PK) and the impact of exposure to the compound on the target microbes (PD). This allows us to optimise dosing regimens to maximise the efficacy of antimicrobial compounds (microbial killing) while minimising toxicity and the risk of the emergence of AMR.

What is the HFIM?

The HFIM is a system of pumps, tubing and microfibers that mimics the body, allowing in vitro assessment of anti-infective compounds under more relevant conditions. It consists of a central reservoir and tubing used as a circulating system, and a hollow fibre cartridge with thousands of permeable capillaries. The extra capillary space (ECS) outside the fibres within the cartridge contains the target organism. During operation, the drug-infused growth medium in the central reservoir is continuously pumped to the hollow fibre cartridge, rapidly passing through the capillaries into the ECS. This continuous flow ensures that nutrients, oxygen, and test compounds are continuously refreshed while waste products are removed. To simulate drug clearance, fresh medium is added to the central reservoir effectively diluting the drug from the system. Accordingly, this balance of drug supply/clearance can effectively simulate the drug’s PK profile.

Why choose the HFIM as PK/PD model?

It is the most capable in vitro system for PK/PD determination for anti-infective compounds, against bacteria and fungi. It is a dynamic model capable of simulating almost any given concentration-time profile for one or more compounds, even if they have very different half-lives.. The Hollow Fibre Infection Model is not limited by in vivo model availability, compatibility of PK profiles, dosing or sampling frequency, or study duration, which is extremely important for understanding PK/PD relationships and the risk of AMR over clinically relevant treatment times. Various cartridges with fibres manufactured from different materials are available to optimise the HFIM for microbial growth and compound performance.

In conclusion, the HFIM is a versatile in vitro PK/PD platform which can accelerate the development of antibacterial and antifungal compounds, contributing to the fight against AMR. 

If you’d like to learn more about the uses of the Hollow Fibre Infection Model you can download our white paper here

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Chikungunya virus, which is transmitted by mosquitoes, can cause disabling chronic arthritis. There are currently no medicines for prophylaxis of Chikungunya, or other viruses transmitted by Aedes mosquitoes, such as Dengue and Zika. Potential therapeutics have been identified, but to perform a successful chemoprophylaxis trial during a short Chikungunya outbreak requires an identified at-risk population. We examined the potential for application of a household transmission model, as used in testing prophylactic drugs against respiratory viruses, included influenza and COVID-19.

In this poster we:

• Set out the evidence for multiple Chikungunya infections occurring per household
• Describe how we are validating the secondary household infection rate
• Show how this could be used in future clinical trials to demonstrate prophylactic efficacy against chikungunya virus infection and other Aedes-mosquito-borne viruses

Read our poster to learn more about our research!

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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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The Hollow Fibre Infection Model (HFIM) is a dynamic in vitro system for the determination of  PK/PD relationships between antimicrobial compounds and bacteria, fungi or viruses.

Evotec has developed its own dedicated state-of-the-art BSL2 facility offering it partners a bespoke in vitro PK/PD service tailored to advance their individual antimicrobial development programs.

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