Meta-analysis is an established statistical technique closely associated with systematic reviews of the literature. The concepts of a statistical meta-analysis are increasingly applied to pharmacometric analysis (model-based meta-analysis). The common feature of both approaches is that the experimental “unit” is a publication and they seek to address the problem of small sample sizes. The Central […]
2011
Design of pharmacokinetic studies for latent covariates
Background: Latent covariates are covariates that are either not available or unobservable at the time of the clinical study. Single nucleotide polymorphisms (SNPs) are of interest in pharmacokinetic studies and are often latent at the time the patient is enrolled. The amount of information provided by latent covariates depends on whether the covariate distribution is […]
Identification and initial evaluation of a prototype clotting time test for enoxaparin
Background: Enoxaparin is a low molecular weight heparin anticoagulant and is widely used in thromboprophylaxis for both prevention of primary thrombosis and at higher doses for treatment in patients with pulmonary embolism, deep vein thrombosis and acute coronary syndromes. Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if […]
Initial exploration of numerical methods for fitting models to PK data
Background: There are well established programs for PK/PD analysis, however, models can get extensive and complex and for parameter estimation are often very time consuming. Therefore, there is a constant need for development of faster methods for model based analysis in terms of definition of the models and the modelling process. The solution to all […]
Utilising prior literature population models to inform clinical practice – a dosing regimen for immediate N-acetyl cysteine treatment of paracetamol overdose
Background: This research project shows how a model from a prior population analysis can be used along with clinical trial simulations to give a clinical rationale for a chosen dosing regimen. Here dosing of N-acetyl cysteine (NAC) after paracetamol overdose is investigated using this methodology. NAC binds covalently to the toxic metabolite of paracetamol, n-acetyl-p-benzoquinone […]
Modelling red blood cell data
Background & Objectives: The survival time of red blood cells (RBCs) is commonly determined based on labelling experiments, where the obtained data is either analysed based on the assumption of a finite and fixed lifespan for all cells, random destruction irrespective of age, or sometimes a combination of both (1). However, it would be desirable to […]
Generalisation of T-optimality for discriminating between competing models – an application to paracetamol overdose
Background and objectives: The T-optimality criterion for model discrimination was introduced by Atkinson and Fedorov [1]. Application of this method required the condition that one of the competing models is correct. We term this criterion local T-optimality. In addition, T-optimal designs are generally not efficient for parameter estimation. The aims of current work are (1) to […]
The effect of surgery on the glucuronidation and sulphation of paracetamol
Intravenous paracetamol is commonly used in the post operative period for the treatment of mild to moderate pain following surgery. The aim of the present study was to investigate the effect of major bowel surgery on paracetamol glucuronidation and sulphation. Patients were given 1 g intravenous paracetamol (10mg/mL) infused over 10 min on the morning […]
Development of a Mechanism-Based Model for the Pharmacodynamics of Daptomycin against Methicillin Resistant Staphylococcus aureus (MRSA)
Objectives: Our objectives were: 1) to develop a mechanism-based pharmacodynamic (PD) model for the time course of total bacterial titer (CFU/mL), obtained in a 1-compartment in vitro infection model (IVIM), in which bacteria (as colony forming units, CFU) are exposed to dynamic concentrations of drug simulating the free-drug profiles predicted for selected candidate regimens in […]
Dexmedetomidine Hemodynamics in Children after Cardiac Surgery
Background: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of this study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. Methods: A […]