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Prof Aleksandra Galetin, Dr A Darwich
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Dosing of analgesic drugs in infants and children is associated with a highly variable and unpredictable exposure and therapeutic effect, as reported for morphine. This high variability in drug exposure in children can partly be attributed to the age-dependency in body composition, ontogeny of drug-metabolising enzymes and transporter proteins. Further, there is a possibility of altered exposure due to drug-drug interactions (DDI) caused by concomitant treatments, as the magnitude of the DDI may vary compared to adults. The net effect of all these factors is not easily predicted using simple dosing algorithms. The management of pain in paediatrics following surgery may be considered a particular safety concern, with inability to communicate pain in younger patients as an added difficulty. As a consequence, an increased risk of medication errors has been observed for children compared to adults.
The advent of precision medicine implies the use of quantitative methods for selecting and optimising drug treatment in patients. Population physiologically-based pharmacokinetic (PBPK) modelling is considered a particularly favourable approach due to its ability to extrapolate exposure between patient population groups by incorporating relevant information on physiology and specific drug properties.
The objective of this project is to employ population-PBPK and pharmacodynamic (PD) modelling of clinical data of analgesic drugs from paediatric patients (infants and children) following surgery. Clinical data for a number of analgesic drugs, including midazolam, morphine and its active metabolite morphine-6-glucuronide, will be provided by our collaborator in Vanderbilt University School of Medicine. Developed PBPK models will consider maturation of enzymatic pathways (e.g., CYP3A, UGT2B7 and other enzymes) in infants and children, with the additional ability to predict the effect of metabolic DDIs. The research proposed aims to further aid precision dosing in paediatric patients in clinical setting. The modelling aspects of this project have strong foundations and build upon previous and ongoing research in our group.
Dr Aleksandra Galetin
http://www.manchester.ac.uk/research/aleksandra.galetin/
Dr Adam Darwich
http://www.manchester.ac.uk/research/adam.darwich/
Centre for Applied Pharmacokinetic Research, University of Manchester:
http://research.bmh.manchester.ac.uk/capkr/
The advent of precision medicine implies the use of quantitative methods for selecting and optimising drug treatment in patients. Population physiologically-based pharmacokinetic (PBPK) modelling is considered a particularly favourable approach due to its ability to extrapolate exposure between patient population groups by incorporating relevant information on physiology and specific drug properties.
The objective of this project is to employ population-PBPK and pharmacodynamic (PD) modelling of clinical data of analgesic drugs from paediatric patients (infants and children) following surgery. Clinical data for a number of analgesic drugs, including midazolam, morphine and its active metabolite morphine-6-glucuronide, will be provided by our collaborator in Vanderbilt University School of Medicine. Developed PBPK models will consider maturation of enzymatic pathways (e.g., CYP3A, UGT2B7 and other enzymes) in infants and children, with the additional ability to predict the effect of metabolic DDIs. The research proposed aims to further aid precision dosing in paediatric patients in clinical setting. The modelling aspects of this project have strong foundations and build upon previous and ongoing research in our group.
Dr Aleksandra Galetin
http://www.manchester.ac.uk/research/aleksandra.galetin/
Dr Adam Darwich
http://www.manchester.ac.uk/research/adam.darwich/
Centre for Applied Pharmacokinetic Research, University of Manchester:
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. Edginton, A. N., W. Schmitt, et al. (2006). "Development and evaluation of a generic physiologically based pharmacokinetic model for children." Clin Pharmacokinet 45(10): 1013-1034.
2. Elkomy, M. H., D. R. Drover, et al. (2016). "Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery." AAPS J 18(1): 124-133.
3. Krekels, E. H., T. N. Johnson, et al. (2012). "From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties." CPT Pharmacometrics Syst Pharmacol 1: e10.
2. Elkomy, M. H., D. R. Drover, et al. (2016). "Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery." AAPS J 18(1): 124-133.
3. Krekels, E. H., T. N. Johnson, et al. (2012). "From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties." CPT Pharmacometrics Syst Pharmacol 1: e10.
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