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Pharmacokinetic Modelling

Understanding the behaviour of your compound in the body

Understanding what the concentration of a compound in the body is and how the concentration varies with time (pharmacokinetics) is an essential foundation of modern drug discovery and development. Taking this further and developing an understanding of how these concentrations are driving in vivo effects (biomarkers/efficacy/toxicity) and the time that these concentrations need to be maintained for a positive outcome starts to allow rational decisions to be made about the dose and pharmacokinetics (PK) profile required in patients. These are the fundamentals of PKPD modelling. This allows a drug developer to answer questions such as:

  • Do I understand my compound’s in vivo activity? If not, what are the sources uncertainty and how does this affect my development strategy?
  • What PK profile do I require?
  • What is my likely therapeutic margin?
  • What is the best dosing regimen?
  • What are the optimal (and most cost efficient) designs for my in vivo efficacy studies?

As a compound progresses into safety testing and especially clinical development there are strong regulatory, and publication needs to describe the pharmacokinetics of a compound. This is initially via non-compartmental analysis (NCA) which is used to establish descriptive statics of the compound’s human pharmacokinetics and provide insight on its performance (for instance does exposure increase proportionally with dose and are the pharmacokinetics time independent?). Focused absorption modelling can build understanding of the properties that effect drug exposure and inform formulation strategies. Alongside NCA characterisation of PK, translational PKPD (pharmacodynamics) modelling can be performed to place emerging clinical data into context with preclinical data, understand potential sources of variability and uncertainty, and guide clinical investment decisions.

As clinical development progresses Population PK and Population PKPD modelling becomes increasingly important to:

  • Identify and describe relationships between a subject’s physiologic characteristics (such as age, weight, gender, ethnicity) and exposure or response (safety / efficacy)
  • Aid clinical trial design
  • Select an optimal dose / schedule that maximises efficacy and minimises safety concerns for future studies

This analysis will be a key part of the argument justifying the choice of Phase 3 and Commercial dose to Regulatory Authorities while also allowing sponsors to understand if different doses are required for different sub-populations.

In later development an area of modelling that is becoming more important is physiologically based pharmacokinetic (PBPK) analyses for biopharmaceutics. Regulators, especially USA FDA, are promoting PBPK as a tool to focus on drug product quality attributes and a mechanistic understanding of their interaction with physiology to affect in vivo drug performance resulting in the definition of critical attributes of the drug product, manufacturing process and input materials. The application of PBPK analyses for biopharmaceutics is considered an important tool to support the more frequent development of clinically relevant drug product specifications

PBPK and allometric scaling
  • Predict human PK exposure
  • Enables dose prediction
  • Understand dosing interval
Absorption Modelling
  • Understand what is required from the formulation the patient takes e.g. best release profile
  • Predict MAD (maximum absorbed drug)
  • Understand how API (Active Pharmaceutical Ingredient) physiochemical properties effect absorption
  • Quantify the risk that candidate drug properties will limit drug exposure in the clinic and safety studies
  • Advise drug formulation strategy to improve exposure
  • Define / support clinically relevant drug product specifications
Preclinical PKPD
  • Understand dose / exposure response relationship in preclinical species and scale
  • Dose to humans
  • Understand the PKPD (exposure / response) relationship to assist with designing clinical studies
  • Improve design of animal studies to reduce cost and increase data
Clinical/Population PKPD
  • Identify and describe relationships between a subject’s physiologic characteristics and exposure or response (safety / efficacy)
  • Aid clinical trial design
  • Select an optimal dose / schedule that maximises efficacy and minimises safety concerns for future studies
  • Justify Phase 3 / Commercial dose
  • Understand dose in sub-populations
Translational PKPD
  • Place emerging clinical data into context with preclinical data to guide clinical investment decisions
NCA
  • Characterise PK parameters for clinical study reports, papers and regulatory documents
  • Allow exposure to be compared with preclinical exposure

Why choose Seda?

Seda’s team of experts has many years of experience of all forms of pharmacokinetic modelling across large pharma and biotech and across late discovery to launch. Seda’s focus is on modelling in real time (rather than a retrospective justification) to aid clear, objective, and decisive decision making. Our PKPD modellers are particularly experienced in the Oncology Therapeutic area. The unique combination of biopharmaceutics, clinical pharmacology and dissolution expertise that resides in Seda alongside our modellers means we are well placed to support PBPK analyses for biopharmaceutics.

Related Position Papers

2021

An introduction to Physiologically Based Pharmacokinetic Modelling and its...

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Position Paper

An introduction to Physiologically Based Pharmacokinetic Modelling and its application in drug development.

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Expertise:

  • DMPK Consultancy and Dose Selection
  • Pharmacokinetic Modelling
  • Complex Medicines
  • CMC Regulatory
  • Clinical Pharmacology
  • Analytical Sciences

Paul A Dickinson

BPharm (Hons) PhD

Chief Scientific Officer & Co-Founder

Paul A Dickinson

BPharm (Hons) PhD

Chief Scientific Officer & 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.

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    Expertise:

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

    Linette Ruston

    BSc (Hons) PhD

    Director: ADME and Modelling Sciences

    Linette Ruston

    BSc (Hons) PhD

    Director: ADME and Modelling Sciences

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    Linette is a Senior Principal Scientist at Seda with a BSc (Hons) and PhD in Chemistry from Universities of Glasgow and Edinburgh, respectively.  She is an experienced Biopharmaceutics and DMPK scientist having spent 17+ years with AstraZeneca where she held roles in Discovery and Early Pharmaceutical Development, providing expert physicochemical, ADME and Biopharmaceutics input into compound design and selection, and applied knowledge of in vitro, in silico and in vivo models to enable material choice and project progression from discovery to early clinical development.  Her current focus is on translation of DMPK/PD and biopharmaceutics understanding into meaningful product and clinical study design within Seda.

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      Expertise:

      • Pharmacokinetic Modelling

      Harri Dickinson

      BSc (Hons)

      Associate Principal Modeller

      Harri Dickinson

      BSc (Hons)

      Associate Principal Modeller

      Harri is able to apply commercially available software PK-Sim, in order to form translational PB-PK modelling for different species or populations and help with dose selection in the early clinical stage settings. As a Mathematics graduate his background enables him to bring systems thinking to PK modelling to identify sources of uncertainty and risk.

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      Expertise:

      • Pharmacokinetic Modelling

      Jake Dickinson

      BSc (Hons)

      Principal Modeller

      Jake Dickinson

      BSc (Hons)

      Principal Modeller

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      A physics graduate, with over 3 years’ experience in the pharmaceutical industry. Jake has applied analytical, mathematical, and problem-solving skills to the assessment of the likelihood of drug candidate success and to identify the likely risks involved in the formulation of a drug. Areas of expertise include PK / PK-PD-TGI modelling in preclinical species and translation to man to aid in dose prediction. Jake has developed models and applications including Nora Max, an in silico absorption model, that aids decision making in late preclinical and early clinical drug development phases of drug development and enables the identification of the formulation technologies required for FiH.

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        Expertise:

        • Pharmacokinetic Modelling

        Jingrao Fei

        BSc (Hons) MSc

        Modeller

        Jingrao Fei

        BSc (Hons) MSc

        Modeller

        BSc in Pharmaceutical Science, MSc in Model-based Drug Development from the University of Manchester. At Seda, Jingrao’s role is to create translational PB-PK modelling for various species or populations and assist with dose selection in early clinical stage settings.

        Expertise:

        • Pharmacokinetic Modelling

        Emily Fell

        MEng (Hons)

        Modeller

        Emily Fell

        MEng (Hons)

        Modeller

        First from the University of Birmingham studying Mechanical Engineering with a final year focus in biomedical engineering. Using my academic background with my interest in this area, I will be working with the modelling team within Seda.

        Expertise:

        • Pharmacokinetic Modelling

        Ashleigh Lomax

        BSc MSc

        Modeller

        Ashleigh Lomax

        BSc MSc

        Modeller

        Ashleigh has a background in both in-silico modelling and chemistry, understanding both compound analysis and the modelling approaches harnessed in drug development. During her MSc, she spent her final months developing a Mechanistic Kidney Model to predict creatinine Drug-Biomarker Interactions (DBIs) aiming to reduce false-positive predictions of Acute Kidney Injury (AKI.)

        In her spare-time, she worked within community pharmacy where she gained a strong understanding of patient welfare and pharmaceutical demand.

         

         

        Expertise:

        • DMPK Consultancy and Dose Selection
        • Pharmacokinetic Modelling
        • Clinical Pharmacology

        Alison Wilby

        BSc (Hons) MSc PhD

        Senior Principal Scientist: Clinical Pharmacology and DMPK

        Alison Wilby

        BSc (Hons) MSc PhD

        Senior Principal Scientist: Clinical Pharmacology and DMPK

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        Alison is a Senior Principal Scientist in Clinical Pharmacology and DMPK at Seda with a PhD in Drug Metabolism from the University of Manchester and an MSc in Toxicology from the University of Birmingham. She is an experienced multidisciplinary scientist having spent over 10 years in DMPK Discovery with AstraZeneca and, for the last 10 years, specialised in PBPK modelling using GastroPlus with Quotient Sciences. At Seda she provides scientific input into Clinical Pharmacology and DMPK study design and provides interpretation and analysis of client data.

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