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Click here to search FindAPhD.com for PhD studentship opportunities(MRC DTP) Development of a precision dosing tool for simvastatin treatment in children and adolescents with dyslipidaemias
Dr K Ogungbenro, Prof Aleksandra Galetin
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
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.
http://www.manchester.ac.uk/research/kayode.ogungbenro
http://www.manchester.ac.uk/research/aleksandra.galetin/
http://research.bmh.manchester.ac.uk/capkr/
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.
http://www.manchester.ac.uk/research/kayode.ogungbenro
http://www.manchester.ac.uk/research/aleksandra.galetin/
http://research.bmh.manchester.ac.uk/capkr/
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on our website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mrc-dtp/.
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1. Wendling T, Dumitras S, Ogungbenro K, Aarons L. Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics. J Pharmacokinet Pharmacodyn. 2015 Dec; 42(6):639-657.
2. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups, Physiologically based pharmacokinetic model for 6-mercaptopurine: exploring the role of genetic polymorphism in TPMT enzyme activity. Br J Clin Pharmacol. 2015 Jul; 80(1):86-100.
3. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups. A physiologically based pharmacokinetic model for Valproic acid in adults and children. Eur J Pharm Sci. 2014 Oct 15; 63:45-52.
4. Gertz M, Cartwright CM, Hobbs MJ, Kenworthy KE, Rowland M, Houston JB, Galetin A (2013) Application of PBPK modeling in the assessment of the Interaction Potential of Cyclosporine against Hepatic and Intestinal Uptake and Efflux Transporters and CYP3A4 Pharm Res 30 (3): 761-780 – 2015 AAPS Meritorious Manuscript Award
5. Tsamandouras N, Dickinson G, Guo Y, Hall S, Rostami-Hodjegan A, Galetin A, Aarons L (2015). Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach. Pharm Res 32(6):1864-83
2. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups, Physiologically based pharmacokinetic model for 6-mercaptopurine: exploring the role of genetic polymorphism in TPMT enzyme activity. Br J Clin Pharmacol. 2015 Jul; 80(1):86-100.
3. Ogungbenro K, Aarons L; CRESim & Epi-CRESim Project Groups. A physiologically based pharmacokinetic model for Valproic acid in adults and children. Eur J Pharm Sci. 2014 Oct 15; 63:45-52.
4. Gertz M, Cartwright CM, Hobbs MJ, Kenworthy KE, Rowland M, Houston JB, Galetin A (2013) Application of PBPK modeling in the assessment of the Interaction Potential of Cyclosporine against Hepatic and Intestinal Uptake and Efflux Transporters and CYP3A4 Pharm Res 30 (3): 761-780 – 2015 AAPS Meritorious Manuscript Award
5. Tsamandouras N, Dickinson G, Guo Y, Hall S, Rostami-Hodjegan A, Galetin A, Aarons L (2015). Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach. Pharm Res 32(6):1864-83
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