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Route of Administration

Small molecule drugs are administered via many different routes, with oral (PO) being the most common due to the ease of dosing in a non-clinical setting and patient compliance. Sygnature Discovery has successfully contributed to the development of many pre-clinical development compounds and investigational medicinal products (IMPs) that have been designed for IV, PO and various topical applications including inhalation, local GI, ocular and dermal.

The intended route of administration should be known at the beginning of a research campaign and each project will need collective input from the Medicinal Chemistry design team, Pharmacology, DMPK and Safety teams. For example, an inhaled drug will likely be a relatively small dose, so may require higher than normal potency. An IV dose needs to have sufficient aqueous solubility and predicted human clearance to allow for a practical infusion rate and volume to be administered to achieve the target plasma concentration.

Each route of administration is likely to need a different screening cascade, with certain assays being front-loaded and taking on a higher importance. At Sygnature Discovery, our scientists have vast practical experience and have been part of successful delivery in all types of different routes of administration. By engaging with us early, we will help you design your screening cascade to maximise the chance of a successful outcome, depending on which dose route is chosen.

IV dosing:

IV therapy is mostly reserved for acute hospital settings and includes oncology and emergency treatment such as myocardial infarction and antibiotic treatment. The hurdle for IV dosing versus PO dosing is arguably lower, but there are key important parameters that must be understood and optimised as part of the design process. These include sufficient aqueous solubility and knowledge of the human clearance, the latter of which can be predicted by DMPK modelling and simulation.

PO dosing:

A simple “once-a-day” oral (PO) therapy is most often sought in a drug discovery campaign. However, ensuring appropriate exposure to ensure maximal target engagement whilst minimising unwanted side-effects is often not straightforward. Poor bioavailability, or unacceptable Cmax:Cmin ratio is very commonly seen, but these issues can, and should, be avoided by engaging with an R&D team that are well versed in all the important inter-dependent drug discovery disciplines from the very beginning. Understanding why bioavailability is unacceptable or not linear with dose are essential to fixing the issue whilst Medicinal Chemistry is active. For example, is poor bioavailability due to a solubility or intestinal and liver metabolism? By engaging with the team at Sygnature Discovery, you will have this expertise at your fingertips from day one of the interaction.

Inhaled dosing:

Various drugs are administered directly to the lungs. The advantages can be near-instantaneous pharmacological response (e.g. bronchodilation), targeted local action, delayed release for prolonging pharmacology, minimising of an unacceptable “liver first-pass effect”, and better safety margins due to a lower dose and systemic exposure. Designing drugs for inhalation require significant specialist expertise and this includes consideration of solubility and dissolution rate, target engagement and PK/PD translation, technical ability in pre-clinical animal studies, and the ability to design compounds with high potency. Sygnature Discovery scientists have many years’ experience of operating in the respiratory administration space with successful clinical advancement.

Other topical dosing routes:

There may be specific reasons for choosing alternative topical dosing routes and these can include direct dermal delivery, ocular (topical or intravitreal), intranasal and local GI delivery. Our scientists have experience of all these delivery routes and the nuances involved in the successful design of compounds depending on dosing route.

 

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