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[NMusers] PhD Studentship in Pharmacometrics at The University of Manchester, Manchester UK

From: Kayode Ogungbenro <>
Date: Fri, 6 Nov 2015 12:38:57 +0000

Development of a precision dosing tool for simvastatin treatment in childre=
n and adolescents with dyslipidaemias

Project Description
Dyslipidaemia is an important etiologic factor in the development of cardio=
vascular disease. Simvastatin is a HMG-CoA reductase inhibitor, commonly us=
ed 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 pharmacokine=
tics is associated with inter-conversion between lactone-acid forms and aff=
ected by multiple metabolic enzymes (CYP3A4) and transporters (OATP1B1, BCR=

The objective of this project is to develop a mechanistic population PBPK m=
odel for simvastatin lactone and acid in children/adolescents with dyslipid=
aemia. The model will allow prediction of simvastatin concentration profile=
s in liver (efficacy) and muscle (toxicity) in this patient population grou=

Although widely used in adults, guidance on the individual dosage regimen o=
f simvastatin in children and adolescents with dyslipidaemia is lacking. Me=
chanistic model that describes accurately complex simvastatin pharmacokinet=
ics in children is essential as a precision dosing tool that would also min=
imise 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 ana=
lysed simultaneously with nonlinear mixed effect modelling approach in NONM=
EM. Clinical data will be provided from our collaborator at Children's Merc=
y Hospital and Clinics, University of Missouri, Kansas City. Information on=
 patients' age, body mass index, LDL level and OATP1B1 genotype will be con=
sidered 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 mo=
delling aspects of this project have strong foundations and build upon prev=
ious and ongoing research in our group.

This 3.5-year full-time MRC DTP studentship provides full support for tuiti=
on 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 =

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 cl=
ass undergraduate degree in a related area. A relevant Masters degree or eq=
uivalent research experience would be an advantage. Any queries regarding t=
he suitability of qualifications should be directed to the primary supervis=

Please direct applications in the following format to Dr Kayode Ogungbenro =
* Academic CV
* Official academic transcripts
* Contact details for two suitable referees
* A personal statement (750 words maximum) outlining your suitability for t=
he study, what you hope to achieve from the PhD and your research experienc=
e 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=

Further details on the MRC DTP scheme and additional PhD project opportunit=
ies can be found on our website:

Kayode Ogungbenro, PhD
Lecturer in Cancer Pharmacometrics | Manchester Pharmacy School | The Univ=
ersity of Manchester | Manchester M13 9PT | United Kingdom
Tel : + 44(0)161 275 2399
Fax: +44(0)161 275 8349

Received on Fri Nov 06 2015 - 07:38:57 EST

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