Thesis
New dose estimation methods and their application in early drug discovery using intravenous, oral and inhaled routes of administration for new chemical entities
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2019
- Thesis identifier
- T15971
- Person Identifier (Local)
- 201177877
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- The pharmaceutical industry continues to face mounting fiscal, political and regulatory challenges developing the next generation of innovative medicines. Drug discovery scientists are directly challenged with the task of trying to overcome the challenge of poorR&D productivity by improving the quality of new chemical entities progressing into drug development to reduce drug attrition. This project focusses on early drug discovery and investigates the potential of a concept called Drug Efficiency (DE). DE was originallyintroduced by the Psychiatry CEDD (Centre of Excellence for Drug Discovery at GlaxoSmithKline) as an in vivo pharmacokinetic (PK) and PK-pharmacodynamic (PD) parameter to try and improve the quality of compounds progressing into in vivo PKPD models.The aim was to select compounds which would achieve higher free concentrations in the CNS, and therefore increase target engagement and improve efficacy. The focus of thisproject was to show how DE (and it’s in vitro biomimetic derived equivalent HPLC DEmax) can be used for projects involving intravenous (IV), oral and pulmonary routes of administration to select compounds with improved physicochemical properties (low MW, lipophilicity and solubility) and therefore more likely to have a low efficacious clinical dose during early lead optimisation.The combination of HPLC DEmax and in vitro potency makes it possible to estimate a clinical dose that would result in an efficacious steady-state free concentration at the site of action. The influence of the potential discrepancies between the in vitro and a later stage in vivo DEmax, the whole blood potency, volume of distribution and clearance on the dose estimation has been investigated using data from a GSK programme profiled during lead optimisation. It was found that drug potency had the greatest influence on estimating the clinical dose. When the estimated dose was low, the impact of small changes in PK parameters such as the volume of distribution and clearance had less effect and typically did not affect compound ranking. For inhaled pulmonary drugs, the physicochemical and PK properties are often considered to be the opposite of drugs administered by the IV and oral routes. Thebiggest challenge in the design of inhaled drugs is achieving the optimum balance of lung retention and pharmacological duration of action without causing lung toxicity. Unlike extravascular drugs, where there have been multiple physicochemical analyses andconcepts proposed to help select the right balance of properties for successful drug design, there are very few drug design concepts beyond solubility and permeability for inhaled drug design. This project shows how HPLC DEmax can be used as a third criticalparameter alongside solubility and permeability to help design inhaled small molecules which have “intrinsic” lung retention, pharmacological duration of action and improved lung safety.Lung retention was measured for a set of small molecule JAK inhibitors, which all had similar solubility and permeability, but different intrinsic lung retention. It was found that compounds with drug efficiencies (DEmax) of around 1% had extended lung exposure. Introducing DEmax as an additional parameter has shown that biomimetic binding can provide further information to help identify compounds with the improved potential to become drug candidates with the desired lung residency when administered via the pulmonary route.
- Advisor / supervisor
- Johnston, Blair
- MacKay, Simon
- Eddershaw, Peter
- Resource Type
- Note
- Previously held under moratorium in Chemistry department (GSK) from 3 May 2019 until 18 June 2021.
- DOI
- Funder
Relações
Itens
Miniatura | Título | Data de carga | Acesso | Ações |
---|---|---|---|---|
|
PDF of thesis T15971 | 2021-09-17 | Público | Baixar |