Mechanism-based modelling of the response from hypermutable cystic fibrosis Pseudomonas aeruginosa isolates to inhaled aztreonam and tobramycin dosing regimens simulated in a dynamic biofilm model

Background Hypermutable, resistant and biofilm forming Pseudomonas aeruginosa proves challenging to treat in patients with cystic fibrosis (CF). Understanding biofilm killing and regrowth is important for the selection of effective antibiotic dosing regimens. Aim To develop a mechanism-based model (MBM) which characterises the time-course of planktonic and biofilm bacteria in response to aztreonam and tobramycin […]

Time Course of Procalcitonin Concentration Following Birth and Surgery

Introduction: Procalcitonin plasma concentration (PCT) has been suggested as a biomarker for acute infection (usually bacterial). Concentrations increase rapidly within 4-6 hours of infection [1]. However PCT also increases following events such as birth and surgery without any known infection [2, 3]. It is important to understand the time course of PCT following these events […]

Cefazolin pharmacokinetics and extent of device binding during cardiopulmonary bypass

Introduction: Cefazolin is administered routinely for antibiotic prophylaxis during cardiac surgery. However there is uncertainty in determining the correct dose due to the impact of critical illness and the cardiopulmonary bypass (CPB) machine on drug pharmacokinetics (PK). Aims: To quantify cefazolin adsorption to the CPB machine device and incorporate this into a population PK model […]

A population pharmacokinetic model of once daily intravenous busulfan in paediatrics characterising time-dependent clearance

Aims: To characterise the pharmacokinetics of busulfan in paediatrics and investigate changes in clearance over a 4-day treatment course of once daily intravenous therapy. Methods: A population pharmacokinetic model was developed using NONMEM®, based on first-order conditional estimation with interaction, in patients ≤18 years receiving once daily intravenous busulfan for haematopoietic stem cell transplant (HSCT) who had […]

External evaluation of population pharmacokinetic models of tacrolimus in adult heart transplant recipients

Background. Numerous population pharmacokinetic (popPK) models of tacrolimus (TAC) in adult transplant recipients have been published. However, data on the accuracy of Bayesian forecasting with concomitant azole therapy or extrapolation to other transplant cohorts are scarce. Aims. To externally validate the predictive performances of relevant popPK models of TAC in adult heart transplant (HTX) recipients […]

The Influence of Genotype on Warfarin Dose Predictions

Background & Aims: Warfarin is the most commonly prescribed oral anticoagulant worldwide, however, a narrow therapeutic range poses a barrier to safe and effective therapy. Common methods to predict warfarin dose requirements are biased at the extremes. When evaluated by simulation, Bayesian dose forecasting using a theory-based warfarin PKPD model achieves unbiased and precise dose predictions […]

Total and unbound mycophenolic acid pharmacokinetics before and after kidney transplantation

Background: An increased incidence of acute rejection is seen with underexposure to mycophenolic acid (MPA) in the initial week post kidney transplantation, particularly in high immunological risk patients (1,2). Up to 25% of individuals in contemporary drug regimens are below the proposed therapeutic range at this time (3), and these individuals cannot be identified a […]

Mechanism-based PK/PD modelling approach to optimise combination dosage regimens against multidrug-resistant clinical isolates of Pseudomonas aeruginosa and in-vivo evaluation in a murine thigh infection model

Aims: Pseudomonas aeruginosa (Pa) is an opportunistic Gram-negative pathogen that is prevalent in bloodstream, wound and respiratory infections and has a high propensity to become multidrug-resistant. Our primary aim was to systematically evaluate synergistic killing and suppression of resistance of Pa by combinations of carbapenem plus aminoglycoside (AGS) antibiotics. Secondly, we sought to propose optimised […]

Time-to-event model of leflunomide cessation due to toxicity in rheumatoid arthritis patients: Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with cessation.

Aim(s) Leflunomide is used in the treatment of rheumatoid arthritis (RA), yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort, and to investigate potential predictors of cessation such as total and free teriflunomide exposure and […]