Model-based Drug Development

This unit provides further training on the use of mechanistic pharmacokinetic models, which use mathematical descriptions of physiological processes to predict the fate of drug molecules within the human body. Completion of the introductory module (PHAR69922) is an essential prerequisite.

The unit addresses two key aspects of IVIVE and PBPK models: 1) developing mathematical representation of key chemical and physiological processes that affect drug molecules in the body, and 2) defining the relationships that link these processes.

Conceptual and theoretical understanding is developed through lectures. Hands-on workshops with flipped-classroom approach promotes independent and active learning as students gain hands-on experience with relevant software and enables parallel teaching and assessment of full-time (on-campus) and part-time/ CPD (distance learning) student cohorts. Implementation of this approach will be described in the following areas:

• Prediction of drug-drug and drug-disease interactions in special populations such as neonates, children, patients with kidney or liver impairment
• Special considerations for endogenous biomarkers, biologics, PBPK- pharmacodynamic models (PBPK-PD), and biopharmaceutics

Topics outline

• Complex drug interactions involving transporters and endogenous biomarkers
• PBPK modelling in special populations, including paediatrics and organ impairment
• PBPK M&S of biologics
• PBPK M&S for biopharmaceutics
• Regulatory considerations for PBPK modelling
• Best practices including sensitivity analysis and parameter estimation
   

The unit aims to provide students with training in the following areas:

• PBPK modelling skills: Students will be able to derive, implement, and apply physiologically based pharmacokinetic (PBPK) models to various pharmaceutical contexts, including the use of relevant software tools.
• Regulatory and Best Practices: Students will understand the regulatory requirements and best practices for PBPK modelling and be able to conduct sensitivity analyses and parameter estimation as part of PBPK model development
• Advanced Topics in PBPK modelling: Students will be able to analyse and interpret data related to the in vitro-in vivo extrapolation (IVIVE)-linked PBPK models in multiple application areas, including in transporter-mediated drug-drug interactions (DDIs), endogenous biomarkers, biologics, biopharmaceutics, and special populations

The unit is delivered over a 12-week period and will include:

• Lectures, including external speakers from PBPK software companies
• Workshops
• eLearning materials support independent completion of activities
• Journal club (student seminars)
• Drop-in sessions (office hour, optional)
• Webinars (part-time students only)
• Directed reading
• Summative-assessed coursework (x 2)
• Written exam

Students should be able to: 

• discuss examples of how in vitro- in vivo scaling methods for transporters are currently being used to guide drug development
• describe how physiological modelling provides insight into drug-development problems such as drug-drug interactions
• describe the specific challenges and modelling approaches that arise in coping with special patient populations and special classes of drug such as biologics and biopharaceutics.

Students should be able to: 

• critically analyse observations on plasma drug concentration-time profiles and characterise them quantitatively for the purpose of making inferences between different drugs, different patients, different conditions etc
• identify the reasons for differences in the time-courses of drug effect and plasma drug concentration
• make informed predictions of the behaviour of drugs in body with respect to plasma drug concentration-time profile
• critically assess applications of physiologically based modelling and make judgements about acceptable use of such models.

Students should be able to:

• perform calculations using equations for in vitro- in vivo scaling
• use specialised computer software Simcyp and Matlab along with more general data analysis/presentation software to simulate and explore the effects of covariates on drug and metabolite concentrations in the body.

Students should be able to:

• extract key points from scientific literature
• effectively use written and verbal communication.

Core textbook: “Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry” by Sheila Annie Peters, 2021; DOI:10.1002/9781119497813

Lecture notes cite key research articles and reviews, which include…

• Houston, J.B. and A. Galetin (2008) Methods for predicting in vivo pharmacokinetics using data from in vitro assays. Curr Drug Metab. 9:940-51.
• Rostami-Hodjegan, A. (2012) Physiologically Based Pharmacokinetics Joined With In Vitro-In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology. Clin Pharmacol Ther 92:50-61.
• Rowland, M., C. Peck, and G. Tucker (2011) Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 51:45-73.
• Zhao, P., M. Rowland, and S.M. Huang (2012) Best practice in the use of physiologically based pharmacokinetic modeling and simulation to address clinical pharmacology regulatory questions. Clin Pharmacol Ther 92:17-20.
• Tsamandouras, N., A. Rostami-Hodjegan, and L. Aarons (2013) Combining the "bottom-up" and "top-down" approaches in pharmacokinetic modelling: Fitting PBPK models to observed clinical data. Br J Clin Pharmacol. 79:48-55
• Chu, X., et al. (2022) Clinical implications of altered drug transporter abundance/function and PBPK modeling in specific populations: an ITC perspective. Clinical Pharmacology & Therapeutics 112:501-526.