Background: Identification of appropriate covariate(s) in population PK-PD modelling is a key requirement to account for between subject variability (BSV). Total body weight (WT) is often considered an important covariate for clearance (CL). Models that link CL to WT vary in the literature and typically include linear (exponent = 1) and nonlinear scaling (exponent = […]
2017
Improving gentamicin dosing in paediatric oncology patients
Objective: To develop and apply a population PK model of gentamicin in paediatric oncology patients in i) a utility function approach that balances the probability of efficacy against potential kidney damage related to gentamicin accumulation in the renal cortex and ii) a semi-mechanistic modelling approach to simulate bacterial killing over time under different doses; with […]
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 […]
Understanding the sensitivity of international normalized ratio (INR) to variations in clotting factor levels
Background: International normalized ratio (INR) is an in vitro blood test designed to measure the clotting time of blood. The INR represents the activity of several clotting factors including fibrinogen, prothrombin (factor II), factor V, factor VII, and factor X. As a global measure of coagulation, the INR is unable to delineate the contributions of […]
Population Pharmacokinetic Model of Doxycycline Plasma Concentrations – Pooled Study Data
Background Doryx MPC is a novel Mayne Pharma formulation of the oral tetracycline antimicrobial doxycycline. Doryx MPC has increased acid resistance compared to the standard Doryx tablet, which will minimise oesophageal and stomach dissolution and thus is anticipated to reduce irritation in those regions. The literature is presently void of a population pharmacokinetic analysis of […]
Comparison of Non-Compartmental and Mixed Effect Modelling Methods for Establishing Bioequivalence for the Case of Two Compartment Kinetics and Censored Concentrations
Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool […]
Infliximab maintenance dosing in inflammatory bowel disease: an example for in silico assessment of adaptive dosing strategies
Background: Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory bowel diseases. Unfortunately, not all patients demonstrate an initial response during induction, whilst others respond initially but relapse within one year of treatment. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop antibodies […]