The Centre for Applied Pharmacokinetic research (CAPKR) is a consortium of academic researchers at The University of Manchester and eight industrial pharmaceutical companies.
Our mission is to understand what happens to drugs when they enter the body – where they go, how they are metabolised and how quickly. In particular, we seek to understand how differences of genetics, lifestyle and disease affect what happens to drugs.
This understanding leads to more appropriate drugs and dosing for each patient (so called 'precision medicine') and more economic use of drugs by the NHS and other healthcare providers.
What we do
- We quantify the proteins responsible for the metabolism and transport of drugs in the body, by various proteomic methodologies, mainly based on tandem mass spectrometry.
- We determine activities of human and animal drug metabolising enzymes and transporters using different in vitro systems. We use in silico models to extrapolate from in vitro to in vivo (IVIVE).
- We use such models to predict pharmacokinetic parameters for different drugs in different groups of patients.
- We determine effective, safe and economical dose regimes for different groups of patients.
Our industry collaborators
The CAPKR industrial consortium was established in 1996 by Professor Malcolm Rowland at The University of Manchester to generate a centre of excellence in research and training of pharmacokinetics, and engage in problems of interest to the pharmaceutical industry.
Our current industry partners include:
AbbVie is a research-based global biopharmaceutical company committed to developing innovative, advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. But we do more than treat diseases. With ~30,000 employees and marketed products in more than 175 countries, we aim to make a remarkable impact on people’s lives.
The DMPK-BA organization plays a vital role in increasing probability of success of AbbVie's pipeline, supporting early Discovery and continuing through all phases of clinical development. We provide:
- Mechanistic understanding of ADME; in vitro ADME, CYP/transporter and biotransformation data
- Prediction of human exposure, formulation/food effects, DDI (PBPK modeling)
- FIH dose recommendation and efficacious dose regimen prediction
- Target assessment/quantification using proteo(geno)mics
- Preclinical and Clinical Biomarker, PK (small and large molecules), and Immunogenicity bioanalysis
- Mechanistic understanding of efficacy and safety endpoints through translational modeling and simulation (PK/PD; Quantitative System Pharmacology)
DMPK-BA is the driving force of Translational Science, bringing transformative medicines to patients.
Lilly focus internal research efforts primarily on four core therapeutic areas: specialty care, diabetes, oncology and animal health. They also continue to pursue innovative science and new opportunities beyond our targeted disease categories.
A member of the Roche Group, Genentech has been at the forefront of the biotechnology industry for more than 40 years, using human genetic information to develop novel medicines for serious and life-threatening diseases. Genentech has multiple therapies on the market for cancer & other serious illnesses.
The Drug Metabolism and Pharmacokinetics (DMPK) group at Genentech is dedicated to enabling the discovery, development and commercialization of safe and effective medicines by elucidating the absorption, distribution, metabolism, excretion and pharmacokinetic properties of small molecule drug candidates. We accomplish this through the application of state of the art technologies, leveraging both internal and external collaborations.
GSK are a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer.
They have 3 global businesses that research, develop and manufacture innovative pharmaceutical medicines, vaccines and consumer healthcare products.
Janssen focus their efforts and resources where the need is high, the science is compelling and where they have the greatest opportunity to save and improve lives.
Merck is a leading science and technology company in healthcare, life science and performance materials. As the largest of Merck’s three business sectors, Merck Healthcare has about 20,000 employees around the world work in Europe, North America, Asia, Africa and Latin America and is dedicated to driving innovation in science and technology for real improvement of patients' lives.
The biopharma portfolio of the healthcare sector focuses on the therapeutic areas of oncology, neurology, immunology, fertility, general medicine and endocrinology.
PBPK models of gastrointestinal and hepatic cancers
Cancer patients are characterised by high drug exposure variability.
The aim of this project is to create virtual cancer patient populations, in order to understand the variability of drug metabolism in cancer patients, and predict the disease impact on the gastrointestinal and hepatic cancers.
This will be achieved firstly through the quantification of DMEs and transporters by using LC-MS/MS.
These measurements will be incorporated into PBPK models and the models will be validated by the assessment of the disease impact on small molecule anti-cancer drugs. The overall accomplishment will be the improvement of cancer population profiles in existing PBPK models.
Project by PhD student Areti Vasilogianni.
For more than a century, MSD has been inventing for life, bringing forward medicines and vaccines for many of the world's most challenging diseases. Today, MSD continues to be at the forefront of research to deliver innovative health solutions and advance the prevention and treatment of diseases that threaten people and animals around the world.
The Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism within MSD seeks to bridge in vitro and preclinical knowledge to human drug exposure and response across all stages of drug development.
To this end, we are collaborating with CAPKR to find innovative solutions for challenging problems in translational research.
Takeda Pharmaceuticals is a global company with a 236 year long, rich drug discovery and development history. Takeda always conducts drug discovery/ business based on its core values (Takeda-isms) and priorities.
Takeda-ism (integrity, fairness, honesty, perseverance) and the four priorities (patient, trust, reputation, business) are deeply ingrained in Takeda’s ways of working to ensure its commitment to quality and that Takeda does the right thing – at all times.
Takeda focuses on four major therapeutic areas including neuroscience, gastroenterology, vaccines, and oncology. An additional therapeutic area, rare diseases, will soon be added to Takeda’s portfolio. Takeda is and will continue to aspire to bring better health and a brighter future for people worldwide.
Potential industrial partners
CAPKR has around 10 post-doctoral associates, 20 PhD students and several visitors working on various projects related to our mission. Here are just a few of them.
Optimising prediction of clearance for low-turnover drugs
Metabolic turnover of prospective drug compounds which are slowly cleared is difficult to quantify.
Recent progress in long term hepatocyte culture systems, experimental methodology for resolution of drug uptake and metabolism, together with cross species approaches will be explored for a prototypical panel of drugs with the intention of integrating and optimising these emerging methodologies.
A two-year postdoctoral position is available.
Lead: Dr David Hallifax
Industry collaborator: CAPKR industry-sponsored project
Innovative tool for personalised treatment of patients with neovascular age-macular degeneration
With an ageing population, illnesses that threaten healthy vision are increasing. For example, age-related macular degeneration (AMD) is expected to affect 288 million of the worldwide population by 2040.
The treatment of neovascular AMD consists of regular injections of anti-VEGF drugs into the eye ball for the rest of a patient's life.
However, the dosing intervals vary widely among the patients and there is no quantitative method for evaluating the injection frequency.
For that, computational tools linking the drug dose regimen and the drug effect in the retina are needed. Using population pharmacokinetic-pharmacodynamic (PK-PD) and optical coherence tomography (OCT) imaging technique is a new, novel and promising approach.
Lead: Dr Eva Maria del Amo Paez (working with Professor Leon Aarons and Professor Amin Rostami)
Industry collaborator: Certara
Additional funders: H2020-EU.1.3.2. Marie Skłodowska-Curie fellowship - Nurturing excellence by means of cross-border and cross-sector mobility
Quantification of human blood-brain barrier drug transporters and solute carriers in health and disease
The blood-brain barrier (BBB) remains a focal point of interest for many scientists who are working on approaches to deliver various therapeutic agents into the brain.
Alterations to BBB proteins can lead to changes in brain function affecting the susceptibility of the CNS to exposure to xenobiotics in the systemic circulation.
Dr Zubida's research focused on the quantification of transporters, enzymes and other proteins at BBB and measurement protein content of the microvascular fraction to populate PBPK model predicting drug disposition and the potential differences in health and disease.
Development of techniques for precision dosing of metabolically-cleared drugs
Liver biopsies are required to assess abundance and activity of enzymes that contribute to the clearance of drugs and other xenobiotics. This can be invasive and alternative methods to enable precision dosing in the clinic are required.
We are therefore developing methods for the quantification of hepatic enzyme abundance in tissue using surrogate analytes in plasma. The approach involves quantifying RNA in isolated plasma exosomes.
Future assessment of specific plasma metabolites is planned.
Industry collaborators: Certara, Thermo, Illumina
Optimising drug regimens in paediatric liver disease using experimentally-derived simulation tools
Funded by the Children's Liver Disease Foundation, the project aims to develop in silico models and simulations of drug metabolism in paediatric populations through examining and quantifying drug metabolising enzymes and transporter proteins.
Using LC-MS/MS-based analysis of liver tissue samples, this project specifically explores the ontogeny of these proteins and how they are affected by comorbidities such as liver disease.
We are in the unique position of having access to neonatal samples with biliary atresia which will provide the data necessary to develop models and ultimately optimise drug regimens in this orphan disease population.
Postgraduate researcher: Martyn Howard
Funder: Children's Liver Disease Foundation
Mechanistic insight into renal and hepatic endogenous biomarkers for transporter‐mediated drug–drug interactions using modelling and simulation
A number of endogenous biomarkers have been proposed for early evaluation of transporter-mediated drug-drug interaction (DDI) risk.
However, there are limited examples of application of modelling and simulation for biomarker qualification.
There is also a lack of understanding of inter-individual variability in biomarker baseline in different populations such as paediatric and chronic kidney disease.
This project aims to develop physiologically-based pharmacokinetic models for endogenous biomarkers of hepatic and renal transporters to inform the optimal design of clinical transporter DDI studies and assess DDI risk in different patient populations.
Currently there is a growing interest in employing advanced 3D systems, e.g. organ-on-a-chip technology, to study renal biology and toxicology and to mimic specific disease states due to its advantages compared to 2D systems.
These systems show promising physiological features and exhibit long-term viability (up to 28 days). However, the application of these novel technologies for mechanistic prediction of renal drug disposition and the translational value remains a challenge.
The objective of this project is to investigate different cellular platforms (in conjunction with mechanistic modelling) as predictive tools for investigating renal drug-drug interactions and nephrotoxicity, in particular associated with OAT1. Specific focus will be on Nortis ParVivo system and its feasibility to study drug transport in the proximal tubule via OAT and OCT transporters.
Postgraduate researcher/PhD student: Thomas van der Made
Industry collaborator: Janssen Pharmaceutica
Translational Imaging in Drug Safety Assessment
Imaging biomarkers, based on non-invasive techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI), offer potential for insights into toxicity issues early on in drug development. One of TRISTAN project aims is to validate the use of gadoxetate as MRI biomarker for assessment of hepatobiliary transporter mediated drug-drug interactions (work package 2).
CAPKR team will perform in vitro evaluation of hepatic uptake of gadoxetate and develop a physiologically based pharmacokinetic model for this imaging biomarker. CAPKR’s expertise in quantitative translation will support the mechanistic interpretation of the in vivo MRI data being generated for gadoxetate, including effects of various transporter inhibitors.
Evaluating protein abundance vs. activity relationships of drug-metabolizing enzymes (CYP and UGT) in the human liver and small intestine
Current approaches for bottom-up prediction of intestinal and hepatic metabolic clearance, including biologically-associated variability, depend on assumption that enzyme activity is proportional to specific protein abundance. This activity-abundance proportionality is assumed to hold irrespective of the organ or patient characteristics. However, there is limited evidence to support this beyond the work done for intestinal and hepatic CYP3A4 (Gertz et al Drug Metab Dispos 2010, 38(7):1147-58).
The project aims to investigate relationship between expression and functional activity of major CYP and UGT drug metabolizing enzymes between human liver and gut. Using CAPKR’s expertise in functional and proteomic analysis, project aims to measure enzyme abundance and activity of specific probes in matched liver and intestinal samples obtained from the same human donors. Implications of the findings on the quantitative translation of drug clearance and drug-drug interactions will be investigated.
Funder: CAPKR consortium-sponsored project
CAPKR staff published 51 articles in the period April 2020 – April 2021. Browse a selection of our publications.
Full title: Physiologically‐Based Pharmacokinetic Modelling of Creatinine‐Drug Interactions in the Chronic Kidney Disease Population
Authors: Hiroyuki Takita, Daniel Scotcher, Rajkumar Chinnadurai, Philip A. Kalra and Aleksandra Galetin
URL: https://doi.org/10.1002/psp4.12566 (2020)
A PBPK model that can account for disposition of creatinine and effects of renal transporter inhibitors in patients with CKD has been developed. The creatinine model enables quantitative translation of renal transporter in vitro inhibition data together with disease‐related changes to predict the extent of changes in SCr in patients with CKD.
Full title: Scaling factors for clearance in adult liver cirrhosis
Authors: Eman El-Khateeb, Brahim Achour, Daniel Scotcher, Zubida M. Al-Majdoub, Varinder Athwal, Jill Barber, and Amin Rostami-Hodjegan
URL: DOI: https://doi.org/10.1124/dmd.120.000152 (2020)
Cirrhosis-specific scalars required for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars can help in predicting drug clearance and selection of dosage regimens for cirrhosis populations. Attempts to consider potential changes have been empirical and ignored the potential impact of the cause of cirrhosis. This study provides experimental values for these scalars for the first time and assessed their impact on predicted exposure to various substrate drugs using physiologically-based pharmacokinetics simulations.
Full title: PBPK model of coproporphyrin I: Evaluation of the impact of SLCO1B1 genotype, ethnicity, and sex on its inter-individual variability
Authors: Hiroyuki Takita, Shelby Barnett, Yueping Zhang, Karelle Ménochet, Hong Shen, Kayode Ogungbenro and Aleksandra Galetin
URL: https://doi.org/10.1002/psp4.12582 (2020)
A PBPK model for coproporphyrin I (CPI), an endogenous biomarker of hepatic OATP1B transporter, has been developed by accounting for the impact of SLCO1B1 genotype, ethnicity, and sex on the disposition of CPI. Modeling of CPI maximizes the sensitivity of this biomarker to evaluate OATP1B1 interaction potential as early as in first-in-human studies and to facilitate the design of prospective interaction studies with corresponding clinical probes.
Full title: Hepatic scaling factors for in vitro-in vivo extrapolation (IVIVE) of metabolic drug clearance in patients with colorectal cancer with liver metastasis
Authors: Areti-Maria Vasilogianni, Brahim Achour, Daniel Scotcher, Sheila Annie Peters, Zubida M. Al-Majdoub, Jill Barber, Amin Rostami-Hodjegan
Journal: Drug Metabolism & Disposition (2021)
This study presents, for the first time, scaling factors for IVIVE of metabolic drug clearance in cancerous and matched histologically normal livers from colorectal cancer liver metastasis patients. The application of the measured scaling factors on PBPK simulations of various metabolically cleared drugs demonstrate the necessity of population-specific scaling for model-informed precision dosing in oncology.
Full title: Dose individualisation in oncology using chemotherapy-induced neutropenia: Example of docetaxel in non-small cell lung cancer patients.
Authors: Lombard A, Mistry H, Aarons L, Ogungbenro K.
URL: https://doi.org/10.1111/bcp.14614 (2020)
Chemotherapy-induced neutropenia has been associated with increase in overall survival and it is also directly linked to toxicity in non-small cell lung cancer patients. In this paper we developed an algorithm for dose individualisation of docetaxel, where the risk of toxicity and survival were optimised using neutrophil counts. This algorithm uses information from dose and neutrophil levels after the first dose to optimise toxicity without compromising efficacy.
Full title: Impact of Hepatic CYP3A4 Ontogeny Functions on Drug–Drug Interaction Risk in Pediatric Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study
Authors: Jennifer Lang, Ludwig Vincent, Marylore Chenel, Kayode Ogungbenro and Aleksandra Galetin
The manuscript provides a critical review of applications of paediatric PBPK modelling of CYP3A4 substrates and a performance comparison of two hepatic CYP3A4 ontogeny functions (i.e, Salem and Upreti functions) using ivabradine-metabolite PBPK/PD model. This work highlighted the importance of careful consideration of hepatic CYP3A4 ontogeny function and the implications on labelling recommendations in paediatric population.
Download a list of our publications from April 2020 - April 2021 (PDF, 298KB).
Seven academics make up CAPKR, all providing complementary expertise in applied pharmacokinetic research.
Together they provide experience in both in vitro and in vivo systems, as well as computer-based pharmacokinetics and pharmacodynamics, and omics, especially proteomics and transcriptomics of human and animal tissue.
Amin is well-known for his contribution to translational modelling, such as physiologically-based pharmacokinetics (PBPK).
He is the author of over 230 highly-cited articles, and serves on the editorial board of several journals.
In 2017 he was listed as one of the world’s most highly-cited researchers (in Pharmacology and Toxicology).
Amin collaborates with other members of CAPKR to deliver training for PhD students in involving proteomics, PBPK, clinical pharmacokinetics and pharmacodynamics and precision dosing.
Alex is the recipient of the 2012 ISSX European New Investigator Award. She is very active in the International Transporter Consortium Committee leading in PBPK/translational modelling of transporter kinetics and endogenous biomarkers for transporter drug-drug interactions.
Alex had a sabbatical in the US Food and Drug Administration's Office of Clinical Pharmacology where she provided expert advice on the PBPK modelling of drug-drug interactions and specific populations.
These research activities are also captured in her CAPKR projects.
In recent years Brian has been particularly active through his research and numerous conference presentations in promoting the use of in vitro and in silico systems for predicting human metabolism and pharmacokinetics.
Brian is a member of the editorial boards of several scientific journals, has experience on national science funding bodies and is a consultant to a number of pharmaceutical companies.
He is a Fellow of the American Association of Pharmaceutical Scientists (AAPS) and received the International Society for Study of Xenobiotics (ISSX) 2014 European Scientific Achievement Award.
He has supervised over 60 graduate students. His research publications in the area of drug metabolite kinetics in vivo and in vitro exceed 200 and are highly cited. He was named as a Thomson Reuters Highly Cited Researcher in 2015, ranking among the top 1% most cited scientists in his subject field (Pharmacology and Toxicology) earning him the mark of exceptional impact.
Like many NMR spectroscopists, Jill became a mass spectrometrist in middle age, specialising in quantitative proteomics, particularly as applied to drug metabolism and disposition.
Her group is able to quantify enzymes and transporters in a variety of tissues and thereby feed data-hungry quantitative systems pharmacology models of health and disease.
Apart from research, Jill has won every teaching excellence award the University offers, and is also a National Teaching Fellow.
Kayode Ogungbenro is a Lecturer in Cancer Pharmacometrics and an Honorary Clinical Scientist at The Christie NHS Foundation Trust, Manchester.
His research activities within CAPKR are centred around population pharmacokinetics for top-down (empirical) and bottom-up (PBPK) models.
He is also interested in modelling pharmacodynamic data, optimal design and sample size calculations of population PK studies, population pharmacokinetics in special population (children) and computer aided clinical trial simulation.
Kayode is also the Director of MSc in Model-Based Drug Development which is based within CAPKR.
Leon's major research interests lie in the area of pharmacokinetic and pharmacodynamics modelling.
He has a worldwide reputation in the area of population pharmacokinetics with applications in drug development and drug utilisation in a number of disease states including tropical diseases such as malaria.
Leon is a member of the British Pharmacological Society, a founding member of the United Kingdom Pharmacokinetic Discussion Group and a member of the organising committee of the Population Approach Group Europe.
He is on the editorial boards of a number of journals including Emeritus Editor of the Journal of Pharmacokinetics and Pharmacodynamics.
He has supervised more than 40 postgraduate students, many of which have gone onto positions in academia and the pharmaceutical industry. For more than 20 years he has been teaching pharmacokinetics and pharmacodynamics courses in Europe, Australasia, the United States and Africa.
Dan has research interests in quantitative translation of in vitro data to predict in vivo pharmacokinetic endpoints. He has particular expertise in the use of physiologically-based pharmacokinetic (PBPK) modelling to mechanistically describe and predict drug disposition in health and disease.
After a brief time working in the pharmaceutical industry, Dan completed his PhD at the University of Manchester in 2016, and then visited the US Food and Drug Administration as an ORISE research fellow. He returned to Manchester as a Research Associate working on an Innovative Medicines Initiative project on Translational Imaging in Drug Safety Assessment, and was subsequently appointed as Lecturer in 2019.
Dan is Deputy Director of the MSc in Model-Based Drug Development, which is based within CAPKR.
MSc and CPD courses
MSc and CPD courses in model-based drug development are available at The University of Manchester.
Our current industry partners include:
Students learn from experts at CAPKR and the University's Division of Pharmacy and Optometry.
The MSc in Model-based Drug Development at emphasises mechanistic approaches for the assessment and prediction of pharmacokinetics and pharmacodynamics (PKPD), such as physiologically-based pharmacokinetics (PBPK).
Students will develop the modelling and simulation skills required during drug development, qualifying as a modeller with key skills in computational approaches in pharmacokinetics and pharmacodynamics. This includes experience of the R, Phoenix, NONMEM, MATLAB, Simcyp, and MONOLIX data analysis platforms.
The course also covers structured problems requiring theory and practical skills to solve typical problems that arise in drug development programmes.
The course is available as:
- a one-year full-time course with on-campus teaching;
- a two-year part-time course for off-campus distance learning students, particularly scientists in the pharmaceutical industries who want to expand their expertise.
Learn more and apply
Visit the course page for more information about the course, including a list of units, and details of how to apply:
Our CPD units are designed for science, engineering or mathematics graduates, and scientists linked to the pharmaceutical industry who wish to expand their expertise while working in the industry.
The units are taken from the MSc Model-based Drug Development course and are taught as standalone CPD courses in blocks of either 6 weeks (15 credits per unit) or 12 weeks (30 credits per unit).
Students will develop the knowledge and skills required for making evidence-based decisions at various stages of drug development.
Learn more and apply
Visit the CPD course page for more information, including a list of available units, and details of how to apply:
Events and conferences
Find out more about events and conferences with CAPKR involvement.
CAPKR is delighted to highlight the promotions of two of our academics in 2020, in recognition of their research excellence, leadership and inspirational teaching.
Professor Aleksandra Galetin, Deputy Director for CAPKR, was promoted to a Chair. Alex has published >90 research papers on pharmacokinetics and drug transporters, mentored over 35 PhD students, and was a meeting chair of the 12th International ISSX Meeting (Portland, Oregon; July 2019).
Dr Kayode Ogungbenro, Modelling Lead for CAPKR and Director of MSc in Model-Based Drug Development, was promoted to Senior Lecturer. Kay has published extensively on model-informed precision dosing and optimal study design, particularly relating to oncology and paediatric applications.
We are sure you will join us in our many congratulations to both Alex and Kay on their well-deserved achievements, and we look forward to their continued success.
28 - 31 July 2019
Alex Galetin was in Portland, Oregon for the 12th International ISSX Meeting.
Get in touch to discuss collaborating now.
Contact one of the academic leads listed above.
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