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Predicting Drug Bioavailability with the Modern-day Toolkit

Bioavailability is defined as the fraction of drug reaching systemic circulation following absorption in the gut and first-pass metabolism in the liver. Accurately predicting the bioavailability of orally administered medicines in humans, during pre-clinical development is crucial as it forms the basis for setting safe and efficacious doses in the clinic. This significant parameter is therefore of interest to drug developers and regulatory agencies. Dr. David Hughes and Dr. Yassen Abbas at CN Bio look into predicting drug bioavailability with a modern-day toolkit.

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Predicting Drug Bioavailability with the Modern-day Toolkit

A central pillar in developing new medicines is understanding the pharmacokinetic/pharmacodynamic relationship (PK/PD). Can the drug reach the target site at a sufficient concentration, engage the target, and produce the desired pharmacological effect? For orally administered medications, prevalent in the pipelines of pharmaceutical companies, an important component of the PK/PD relationship is bioavailability. Bioavailability is defined as the fraction of drug reaching systemic circulation following absorption in the gut and first pass metabolism in the liver. Accurately predicting the bioavailability of orally administered medicines in humans, during pre-clinical development is crucial as it forms the basis for setting safe and efficacious doses in the clinic. This significant parameter is therefore of interest to drug developers and regulatory agencies. When oral bioavailability is insufficient, further optimisation of compound structure, changes to formulation or an alternative route of administration may be required, all of which are grounds to discontinue development.

The Need for Improved Bioavailability Predictions

Studies report that PK/PD issues account for 5–10% of clinical failures. Whilst this percentage has fallen significantly over the past 30 years, it remains a concern. Interestingly, a 2014 AstraZeneca study reported that <10% of project teams had a high level of confidence that their drug exhibited “a combination of good drug properties and good pharmacological end points”, where good drug properties include bioavailability. So, which factors drove this fall in PK/PD issues and what can we learn going forward to improve bioavailability predictions?

Firstly, our understanding of the physiochemical properties of compounds with appropriate human PK profiles has improved, and this knowledge is being applied earlier in the discovery process.3 This has been aided by the derivation of absorption, distribution, metabolism, and excretion (ADME) parameters from improved in vitro models, such as the use of suspension cultures of primary human hepatocytes to evaluate liver clearance.

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