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DMPK and Dose Selection

Supporting selection of the best compound for development

In drug discovery it is vital to understand the drug metabolism and pharmacokinetic (DMPK) properties of compounds to identify candidate molecules with suitable properties for development such as:

  • Human dose that is realistic to develop
  • Will remain in the body for long enough / or activity will last long enough so that patient dosing does not have to be too frequent
  • Manageable interaction profile with other drugs the patient will be taking

In silico tools, in vitro assays and in vivo pharmacokinetic (PK) studies are used to characterise compound attributes in terms of absorption, distribution, metabolism, and excretion (ADME). This information, combined with data from in vitro pharmacology assays or in vivo pharmacodynamic / efficacy studies, can be used to predict human therapeutic doses. This process, in conjunction with additional studies designed to identify potential DMPK liabilities, can be used to select the best compound for development.

Seda offer a DMPK consultancy service including:

  • Advice on compound profiling at all stages of drug discovery
  • Identification of issues and compound ranking
  • Analysis of data and linking compound performance to molecule design
  • Compound design to overcome DMPK issues while maintaining activity (multiparameter optimisation)
  • Characterisation of compound absorption, distribution, metabolism, and excretion attributes
    – including design of bespoke in vitro and in vivo studies to answer the specific compound questions
  • Interpretation and scaling of pre-clinical PK data facilitating prediction of human PK profiles
  • Human dose predictions
  • Identification of compound liabilities and performing risk assessments
  • Selection of appropriate vendors and data providers

Why DMPK is fundamental to the drug discovery process:

Sufficient exposure in pre-clinical species must be achieved to test pharmacological hypotheses and toxicity, as well as providing confidence that the drug will deliver the desired therapeutic exposure. Certain attributes or liabilities can heavily influence compound selection, and these should be put into context with knowledge of the target patient population and likely co-medications. Cross discipline collaboration with medicinal chemistry (compound design), pharmacology (delivery of desired pharmacological effect), toxicology (drug safety), pharmaceutical sciences (drug delivery) and service providers (quality data) is key to the discovery of compounds with suitable developability profiles.

Typical Questions that Seda Can Help to Answer:

How good is my molecule?
  • What data is needed to rank compounds, influence compound design or
    support candidate selection?
  • Can the required PK profile be achieved to profile the compound in pre-clinical pharmacology and toxicity studies via the intended route of administration?
  • Will the compound be able to deliver the desired PK profile in humans?
  • What kind of formulation will be needed for pre-clinical and for First in Human studies?
What do I need to build a human dose prediction?
  • What kind of profile is required to deliver the desired therapeutic outcome?
  • How is the compound distributed and eliminated from the body?
  • What data is needed, and which approaches should be used to predict human PK parameters?
  • What kind of modelling is best suited given the data and knowledge available?
  • Which data points are my predictions most sensitive to?
How can I improve the PK profile of the compound?
  • Is low bioavailability due to metabolism, poor solubility, instability, low permeability or efflux?
  • If the drug has a short half-life, what is the reason for this?
  • What can be done to improve compound exposure via formulation approaches or compound design?
  • Which alternative dosing routes or regimens should be considered?
What are the main liabilities of the compound?
  • Which drug metabolising enzymes and drug transporters does the compound interact with?
  • What is the likelihood the compound will be the victim or a perpetrator of a drug- drug interaction?
  • Will any human specific metabolites be formed, or is there any evidence for active or reactive metabolites?
  • Is the drug exposure dependent on the physical form of the compound?

Why choose Seda?

Seda’s team of experts has several years of experience of DMPK across large pharma and biotech assisting in the design and delivery of numerous candidate drugs. Seda has an established network of service providers that can deliver high quality data and can leverage in-house modelling and simulation expertise to understand and predict compound performance in vivo.

Related Publication

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

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Expertise:

  • DMPK and Dose Selection
  • Pharmacokinetic Modelling
  • Complex Parenterals
  • Regulatory CMC
  • Clinical Pharmacology

Paul A Dickinson

BPharm (Hons) PhD

Director & Co-Founder

Paul A Dickinson

BPharm (Hons) PhD

Director & Co-Founder

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Paul has held several senior science leadership roles in Academia and Large Pharma.  These roles focused on applying the best science in projects to ensure optimal product performance in the patient, thus bridging pharmaceutical and clinical disciplines.

 

Immediately prior to founding Seda Pharmaceutical Development Services Paul was Senior Clinical Pharmacology Scientist at AstraZeneca and led the clinical pharmacology program to NDA/MAA for AZD9291/osimertinib, which had been awarded ‘breakthrough therapy’ status by the FDA.  Formerly Paul was a Principal Scientist within Pharmaceutical Development (AZ) leading both the global biopharmaceutics network and the Medicines Evaluation science community (USA, SE, UK).

 

Paul has been at the forefront of recent advances in the understanding of in vitro performance criteria that assure product performance in the patient including clinically relevant dissolution specifications (CRDS).  Paul has co-authored papers with FDA staff focussed on efforts to combine biopharmaceutics with ICH Q8 (BioRAM) and is past Chair of the AAPS ‘QbD and product performance’ focus group.

 

Ask me a question

    Expect a reply typically within 48 hours.

    Expertise:

    • DMPK and Dose Selection
    • Oral Drug Delivery
    • Complex Parenterals
    • Pharmacokinetic Modelling
    • Clinical Pharmacology

    Wang Wang Lee

    MPharm (Hons) PhD GPhC

    Principal Scientist

    Wang Wang Lee

    MPharm (Hons) PhD GPhC

    Principal Scientist

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    Wang Wang Lee is a GPhC registered pharmacist with a PhD in Pharmaceutical Sciences and MBA from the University of Strathclyde. She has deep industry and academic experience particularly in the areas of biopharmaceutics and product development. Her expertise in early and late stage development, risk assessing and mitigating the development challenges has helped clients transition compounds into the clinic from discovery. Most recently, she is interested in DMPK and clinical pharmacology projects for poorly solubles and complex parenterals.

    Ask me a question

      Expect a reply typically within 48 hours.