Model based longitudinal meta-analysis of FEV1 in COPD trials

Background & Objectives: Efficacy benchmarking is an important decision making component during clinical drug development and comparative effectiveness in many countries would ultimately determine ranking and pricing among alternative treatments. In chronic obstructive pulmonary disease (COPD), the forced expiratory volume in 1 second (FEV1) is used to assess lung function [1], and serves as biomarker […]

Development of a simplified mathematical model of the human physiome – An application relating to the cardiovascular system

Background & Objective: The overarching aim of this work is to develop a mathematical model of the human physiome as the basis of an electronic teaching tool for clinical pharmacology. The model is intended to simulate physiological functions and the effect of pathological conditions as well as pharmacological interventions over a time course of up […]

Pharmacokinetics of methotrexate in red blood cells

Background & Objectives: Low-dose methotrexate (MTX) given once weekly is the gold standard in the therapy of rheumatoid arthritis (RA). However, MTX doses required to achieve adequate disease control are highly variable between patients and difficult to predict. MTX polyglutamate (MTXPG) concentrations inside red blood cells (RBCs) have been discussed as a potential biomeasure predicting […]

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 […]

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 […]

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 […]

Statisticians and Pharmacometricians: What can they learn from each other?

Examples are given of how the practice of statistics could be improved if statisticians showed a greater awareness of pharmacokinetic and pharmacodynamic modeling. Some examples are also given where a wider appreciation of statistical theory would improve current approaches to pharmacometrics. Areas in which the two disciplines are in agreement but have failed to have […]

Missing data – the problem of silent evidence

In his bestseller, The Black Swan, Nassim Nicholas Taleb refers to the problem of silent evidence: the graveyard of failed human endeavour that we never visit. To statisticians this problem is known by the more prosaic title of 'missing data'. I consider some famous examples of misinterpretations arising from missing data and lessons one might […]

Population pharmacokinetics of meropenem in burn patients

The objective of this study was to describe the population pharmacokinetic of meropenem in burn patients and to explore the appropriateness of current dosage regimens. Population pharmacokinetic parameters of meropenem in 59 burn patients were estimated using a mixed effect method (NONMEM, ver. 6.2). The final model chosen was a two-compartment model with first-order elimination […]