Introduction: Intravenous ganciclovir (IV GCV) or its oral prodrug, valganciclovir (VGCV), is used for the prevention and treatment of cytomegalovirus (CMV) infection in immunocompromised children. Studies shown a serum area under the concentration-time curve (AUC24) of ≥ 40mg·h/L is required for effective CMV prevention. Aims: To determine a population pharmacokinetic model for immunocompromised children, evaluate […]
PAGANZ ISOP Student Prize for Pharmacometrics
A consistent nomenclature for describing pharmacokinetics and dialyser performance
Introduction: Since renal dialysis machines were introduced into clinical practice in the 1950s, dialysis has immensely evolved to become the core treatment for patients with end stage renal disease. However, quantifying dialysis performance and its effect on medication clearance is still challenging. The Michaels equations, often used to calculate blood dialysance, were derived for 3 different […]
A reduced mathematical model to explore Gi/Gs preferences of the CB1 receptor
Introduction: The cannabinoid type 1 receptor (CB1) induces both Gi and Gs (G-protein) pathways. The Gi pathway inhibits cyclic adenosine monophosphate (cAMP) production and Gs stimulates cAMP responses, the net cAMP response is therefore a mixture of the effects of the two pathways. CB1 shows a preference for the Gi protein and produces a net […]
Improved predictive performance using a model averaging algorithm in model-informed precision dosing of vancomycin
Background: Currently, the recommendation for therapeutic drug monitoring (TDM) of vancomycin is shifting towards AUC-guided dosing through model-based precision dosing (MIPD). However, selecting the correct model is crucial to give appropriate dose recommendations (Broeker et al. CMI, 2019). The aim of the present study was to derive and evaluate a model averaging algorithm (MAA), which […]
Evaluation of the fingerprint profiles of the cannabinoid-1 receptor signalling via a kinetic modelling approach
Introduction: Biased agonism (aka ligand bias) is a term that is used to describe the ability of ligands to differentially regulate multiple signalling pathways when coupled to a single receptor. Quantification of ligand bias is critical to lead compound optimisation. Signalling is affected by rapid ligand-mediated receptor internalisation. Hence, the conventional use of equilibrium models is […]
Evaluation of assumptions underpinning pharmacometric models
Background: All models are underpinned by assumptions. The validity of any inference drawn from a model depends on the appropriateness and likely impact of the underlying assumptions [1]. However, in the literature surrounding quantitative pharmacology models and pharmacometrics, assumptions inherent to model development and use are not routinely acknowledged, described, or evaluated. This casts doubt […]
Internal Deterministic Identifiability of PK and PKPD Models
Introduction: Identifiability analysis is an important aspect of the PKPD modelling framework and is divided into structural and deterministic identifiability. Structural identifiability (SI) relates to the uniqueness of outputs to parameters and inputs. Deterministic identifiability (DI) relates to the precision of parameter estimates. Here we introduce two subcategories of DI: (1) external deterministic identifiability (EDI) […]
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 […]
Identification of continuous covariate relationships
Objective: The objective of this presentation was to demonstrate a new method to identify continuous covariates. The investigation of time after kidney transplant as a covariate on tacrolimus bioavailability was used as an example. Methods: A total of 3100 tacrolimus concentration-time points were obtained from 242 patients who underwent kidney transplantation at Oslo University Hospital […]