The University of Manchester is recruiting a MRC DTP Fully funded PhD call (4 years) for a comparative study of maternal to fetal beta-1 blocker transfer in in vivo and ex vivo models, and data integration with physiologically based pharmacokinetic modelling for prediction of drug disposition.
About the Project
Beta-1 blockers are often prescribed to control cardiac conditions in pregnant women. Despite their use in pregnancy, limited data are available on the effects of these medications on the developing fetus. Although the placenta may provide a partial protective barrier, beta-1 blockers (or their metabolites) may be able to cross the placenta with differing bioavailabilities, due to differences in molecular weight, lipid solubility, transporter-mediated efflux and binding to maternal and fetal plasma protein. The magnitude of transfer of these medications across the placenta can potentially alter fetal growth and cause cardiometabolic diseases in adulthood. The second generation beta-1 blocker, bisoprolol, is the most commonly used agent in pregnant women with cardiac disease in the UK. Our group has shown an association of beta blocker administration with increased rate of babies born small for gestational age. Whether beta-1 blockers of third generations, such as nebivolol, may provide a preferable therapeutical approach is currently underexplored. This project will use pregnant animal models, including rat and sheep, and human placental tissue for a comparative determination of the rate of bisoprolol and nebivolol transfer from the maternal to the fetoplacental circulation in vivo and ex vivo, respectively. Physiological data (including maternal blood pressure, heart rate, uteroplacental and fetoplacental blood flow) will be incorporated into physiologically based pharmacokinetic (PBPK) modelling for prediction of maternal to fetal drug disposition. This approach will take into consideration limitations associated with major differences in placental physiology and structure between species. Important preclinical evidence obtained from this study will provide novel pharmacokinetics of these medications across the placenta, which is essential for understanding potential safety risks for the fetus associated with maternal beta-1 blocker treatments. Integration of in vivo and ex vivo data with PBPK modelling will offer a promising strategy to identify pharmacokinetic changes associated with pregnancy and will provide the necessary information to underpin a future clinical trial looking at treatment superiority (i.e. bisoprolol vs nebivolol) in pregnant women.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – full details on how to apply can be found on the MRC DTP website https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/