Background: Severe sepsis, septic shock and viral/fungal systemic infections are a major challenge for critical care clinicians because of the associated high rates of morbidity and mortality. Adequate antimicrobial therapy is of crucial importance for the survival of these patients. However, unlike many other drugs, anti‐infectives cannot be titrated to effect, as changes in clinical markers usually occur over days. Instead, dosing regimens are based on pharmacokinetic targets that are associated with improved outcome. These targets are related to in vitro inhibitory concentrations for relevant organisms and the class of anti‐infective drug. Correct dosing, therefore, requires consideration of several factors. Dose selection may be even more complex in critically ill paediatric patients whose kidneys may not be mature, but are functionally different from those patients who show acute renal failure. Clearly, dose–response relationships need to be considered to determine the therapeutic window of a drug and to define safe and deleterious concentrations and dosages. In general, these studies are conducted in healthy subjects after which dosing is fine‐tuned in mild to moderately ill patients. Results from these trials are frequently extrapolated for the use in critically ill patients. Such extrapolations presume comparable drug pharmacokinetics (PK) and pharmacodynamics (PD) in critically ill patients compared to patients with rather mild illness. Yet, critically
ill (adult and paediatric) patients may demonstrate multiple organ derangements inciting pathophysiological changes that can affect PK and possibly PD properties of drugs. These changes can occur within an individual patient and may deviate according to the varying stages of illness. In addition, critically ill patients usually receive a wide range of drugs thereby adding to the possibility of drug–drug interactions. Despite these issues, there is limited data to support the evaluation of new dosing algorithms for anti‐infective drugs in neonatal patients.
Objectives: The aim of the project is to evaluate the implications of organ maturation, developmental growth and disease processes on the pharmacokinetics of anti‐infective drugs and the implication of these factors for the dosing regimen in critically ill paediatric patients. Published data from the scientific literature and from historical clinical trials will be used for the purposes of this investigation. Paradigm compounds will be used to illustrate the implications for molecules with different physicochemical, pharmacokinetic and pharmacodynamic properties.
Methods: To investigate the impact of disease processes and organ maturation on drug exposure and clinical endpoints in critically ill paediatric patients, published data on pharmacokinetics, microbiology and clinical response will be reviewed and digitised using a model‐based meta‐analytical approach. Population pharmacokinetic models will be developed using nonlinear mixed effects modelling. Physiologically‐based pharmacokinetic models will also be considered if the approach is deemed feasible. Dosing algorithms will then be evaluated using clinical trial simulations to select the most suitable dose regimen for the target population.
Skills and competencies: In addition to data manipulation (statistical summaries and data visualisation), basic knowledge in (bio) statistics and clinical pharmacology will be required for the successful implementation of the research proposal. Software programs to be used during the project include R and NONMEM v.7.3.
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