http://www.findaphd.com/search/ProjectDetails.aspx?PJID=67654&LID=1030
Development of a precision dosing tool for simvastatin treatment in children
and adolescents with dyslipidaemias
Project Description
Dyslipidaemia is an important etiologic factor in the development of
cardiovascular disease. Simvastatin is a HMG-CoA reductase inhibitor, commonly
used to treat lipid disorders and reduce the probability of a cardiovascular
event. Simvastatin is administered as a lactone and requires conversion to
simvastatin acid to become therapeutically active. Its complex pharmacokinetics
is associated with inter-conversion between lactone-acid forms and affected by
multiple metabolic enzymes (CYP3A4) and transporters (OATP1B1, BCRP).
The objective of this project is to develop a mechanistic population PBPK model
for simvastatin lactone and acid in children/adolescents with dyslipidaemia.
The model will allow prediction of simvastatin concentration profiles in liver
(efficacy) and muscle (toxicity) in this patient population group.
Although widely used in adults, guidance on the individual dosage regimen of
simvastatin in children and adolescents with dyslipidaemia is lacking.
Mechanistic model that describes accurately complex simvastatin
pharmacokinetics in children is essential as a precision dosing tool that would
also minimise the risk of muscle toxicity (the most serious adverse effect).
Model development will be based on our published mechanistic simvastatin model
in adults and will account for physiological differences between populations
and ontogeny of transporters/enzymes of relevance. Plasma concentrations of
simvastatin acid and lactone measured in children/young adults will be analysed
simultaneously with nonlinear mixed effect modelling approach in NONMEM.
Clinical data will be provided from our collaborator at Children's Mercy
Hospital and Clinics, University of Missouri, Kansas City. Information on
patients' age, body mass index, LDL level and OATP1B1 genotype will be
considered as covariates in the model development. Mevalonate will be measured
in plasma samples as a biomarker of HMG-CoA reductase inhibition to allow
comparison of pharmacodynamic effect in children relative to adults. The
modelling aspects of this project have strong foundations and build upon
previous and ongoing research in our group.
This 3.5-year full-time MRC DTP studentship provides full support for tuition
fees, annual tax-free stipend at Research Council UK rates (currently £14, 057)
and conference/travel allowance. The project is due to commence October 2016
and is open to UK/EU nationals only due to the nature of the funding.
The successful candidate will receive training in a wide range of research
skills including quantitative techniques such as modelling and simulation.
Applicants should hold (or be expected to obtain) a minimum upper-second class
undergraduate degree in a related area. A relevant Masters degree or equivalent
research experience would be an advantage. Any queries regarding the
suitability of qualifications should be directed to the primary supervisor
Please direct applications in the following format to Dr Kayode Ogungbenro
([email protected]):
* Academic CV
* Official academic transcripts
* Contact details for two suitable referees
* A personal statement (750 words maximum) outlining your suitability for the
study, what you hope to achieve from the PhD and your research experience to
date.
Any enquiries relating to the project and/or suitability should be directed to
Dr Ogungbenro. Applications are invited up to and including 25 November 2015.
Further details on the MRC DTP scheme and additional PhD project opportunities
can be found on our website: http://www.mhs.manchester.ac.uk/mrcdtp
http://www.pharmacy.manchester.ac.uk/staff/18015
Kay
Kayode Ogungbenro, PhD
Lecturer in Cancer Pharmacometrics | Manchester Pharmacy School | The
University of Manchester | Manchester M13 9PT | United Kingdom
Tel : + 44(0)161 275 2399
Fax: +44(0)161 275 8349
Email:
[email protected]<mailto:[email protected]>
Web:
http://www.pharmacy.manchester.ac.uk/staff/18015