Background. Colistin is administered as its inactive prodrug colistin methanesulfonate (CMS) and is increasingly used as last-line therapy against multidrug-resistant Gram-negative bacteria. While pulmonary dosing of CMS is utilised in lung infections to reduce the risk of nephrotoxicity and neurotoxicity, there is a dearth of pharmacokinetic (PK) information on colistin and CMS. Quantitatively characterising the […]
Abstracts
Individualisation of Leflunomide Dosing in Rheumatoid Arthritis Patients : Development of a Semi-Physiologically Based Pharmacokinetic Model
Objective: Following oral administration, leflunomide is rapidly converted to its active metabolite teriflunomide via blood born metabolism and the CYP enzymes 1A2 and 2C19. Variability in enzymatic activity may contribute to the high variability in total teriflunomide concentrations (3 – 150 mg/L) achieved at standard doses. Leflunomide itself is not detectable in the plasma and […]
Oseltamivir dosing optimisation in patients treated with automated peritoneal dialysis
Background: Peritoneal Dialysis (PD) is a renal replacement therapy commonly used in patients with end-stage renal disease (ESRD). Automated PD (APD) is more convenient than traditional continuous ambulatory PD (CAPD) because the manual delivery and drainage of dialysate is not required. Oseltamivir is an oral prodrug widely indicated for the treatment of influenza infections. The […]
ISoP Lecture 2014: What have models ever done for you?
In this talk I will look critically at the role of modelling within drug research. The theme is basically that many people model for modelling sake without thinking what they are doing. Personally I think this gives modelling a bad name and could be dangerous (but probably not). I will go through a number of […]
Estimating the relative potencies of an anticholinergic medicine: A methodological view point
Background Older people continue to be prescribed medicines with anticholinergic properties and are at an increased risk of experiencing adverse events with these medicines.1 Exposure to 1 or more medicines with anticholinergic properties is termed anticholinergic burden.2 Tools to quantify anticholinergic burden have been developed, but the major drawbacks of these tools are the limited […]
Development of a criterion to quantify forgiveness
Background: A variety of patterns of imperfect adherence have been reported including deviations in timing of doses as well as non-consecutive missed doses and drug holidays [1]. Forgiveness is a drug specific property that arises from the relationship of the duration of action and the dose interval of the drug. When the duration of action […]
Population pharmacokinetic model for D-β-Hydroxybutyrate following ketone monoester ingestion
Background: Ketone bodies, the evolutionary response to starvation in humans, are produced in the liver from fatty acids in response to low blood glucose and insulin, and used by the body as fuels. Ketogenic diets have long been used to treat intractable paediatric epilepsy, with therapeutic evidence for ketosis in other neurodegenerative disorders such as […]
Simplification of a pharmacokinetic model for red blood cell methotrexate disposition
Background: Methotrexate (MTX, MTXGlu1) is the gold standard treatment of rheumatoid arthritis. The time course of clinical outcomes is difficult to predict after commencing oral or subcutaneous MTX treatment. A 9-compartment pharmacokinetic (PK) model is available for describing the time course of the concentrations of MTXGlu1 and its polyglutamated metabolites (MTXGlu2-5) in red blood cells […]
ISoP Lecture 2013: “Broadening the Impact” – Identifying Some Novel Clinical Applications of Pharmacometrics Research
The background, approach and challenges to conducting pharmacometrics research in four novel therapeutic scenarios are described all of which are currently being investigated by the presenter’s research team: “Therapeutic Hypothermia and Anticonvulsant Pharmacokinetics in Newborn Infants with Hypoxic Ischemic Encephalopathy HIE)”, “Melatonin Pharmacokinetics in Tetraplegia”, “Modeling Fetal Drug Exposure”, “A Thymine-Based PK Screening Test for […]
Semi-mechanistic PKPD model of thrombocytopenia characterizing the effect of a new histone deacetylase inhibitor (HDACi) in development, in co-administration with doxorubicin.
Objective: Recent studies [1, 2] demonstrated that the combination of an HDAC inhibitor and DNA-damaging agents has synergistic effects to induce apoptosis. This observation is of potential clinical applicability although several dose-limiting toxicities need to be pre-assessed before dose optimization. The study aim was to develop a PKPD model of thrombocytopenia that considered the PK […]