(MRC DTP) Model-based precision dosing of levofloxacin in critically ill patients

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in adults and children worldwide1. In the UK, CAP accounts for over 100,000 hospital admissions annually. Levofloxacin is a broad spectrum antibiotic licenced for the treatment of CAP. Resistance of levofloxacin is increasingly identified in patients with CAP. The current, fixed dose of levofloxacin was established in early phase trials of healthy volunteers and non-critically ill patients. Antibiotic pharmacokinetics has been demonstrated to be different in critically ill patients compared to healthy volunteers with marked between subject variability. Between-subject variability results in under-dosing and treatment failure in a significant proportion of patients. The optimal dose of levofloxacin in critically ill patients with CAP is still not clearly defined.

The objective of this project is to develop a model-based precision dosing algorithm for levofloxacin in critically ill patients to improve treatment outcome, using mechanistic model that account for between-subject variability in the pharmacokinetics.

The pharmacokinetics of levofloxacin has been studied in in-vitro models, heathy volunteers and critically ill patients. Measurements of levofloxacin in the plasma and epithelial lining fluid of the lung, as the primary site of action, allows assessment of intrapulmonary penetration in patients with CAP. In this project, a mechanistic compartment model will be developed to describe drug concentrations in plasma and the lung, as well as drug transfer between compartments. A mixed-effect modelling approach will be used, which is the gold standard for data analysis in clinical pharmacology especially during drug development. The model will use demographic and pathophysiological factors to explain differences in drug exposure between individuals, especially between healthy volunteers and critically ill patients.
Simulation will be used to:
1. Explore the link between drug exposures in patients and the levofloxacin concentration associated with bacterial killing for common causative CAP pathogens, in a pharmacokinetics-pharmacodynamics paradigm
2. Identify alternative levofloxacin dosage regimens
This research aims to provide a clinically applicable tool to personalised dosing in critically ill patients. The data for this project have been obtained from a number of clinical studies (four) in healthy volunteers and critically ill patients (105 subjects in total), following administration of oral and intravenous doses Clinical results from these studies have been published, but not used to develop mechanistic model which is the subject of this project.
References:
1. NICE guideline. Pneumonia in adults: diagnosis and management. 2014.

https://www.research.manchester.ac.uk/portal/kayode.ogungbenro.html
https://www.research.manchester.ac.uk/portal/adam.darwich.html
https://www.research.manchester.ac.uk/portal/tim.felton.html
https://www.uhsm.nhs.uk/consultants/timothy-felton/

Entry Requirements
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.