Determination of the pharmacodynamics of vancomycin in young infants via time-to-event analysis

Introduction: Coagulase-negative staphylococci (CoNS) are a leading cause of late-onset sepsis in young infants. Vancomycin is commonly used for the empirical treatment of CoNS. However, the therapeutic target for these bacteria is poorly defined and is currently extrapolated from data for methicillin-resistant Staphylococcus aureus (MRSA) in adults and older children (1). Further understanding of the […]

Evaluation of the fingerprint profiles of the cannabinoid-1 receptor signalling via a kinetic modelling approach

Introduction: Biased agonism (aka ligand bias) is a term that is used to describe the ability of ligands to differentially regulate multiple signalling pathways when coupled to a single receptor.  Quantification of ligand bias is critical to lead compound optimisation.  Signalling is affected by rapid ligand-mediated receptor internalisation.  Hence, the conventional use of equilibrium models is […]

Kinetic modelling of ligand mediated internalisation

Introduction: Internalisation is by its nature kinetic.  Hence, application of the standard assumption of equilibrium conditions used by pharmacologists to determine the equilibrium constant (KD) is not obvious for either the ligand-mediated internalisation pathway or other functional assays that occur over the same timeframe as internalisation.  However, it is also difficult or impossible to estimate […]

Identifiability analysis of empirical models used for quantifying “biased” ligands

Background: Model identifiability is an important attribute that a model must satisfy in order to derive the meaningful interpretation of estimated parameters.  In general, there are two types of identifiability: structural and deterministic.  Structural identifiability is rooted in the underlying mathematical structure of model.  Deterministic identifiability is concerned with the study design and its execution. […]