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 […]
Abstracts
Application of reported arbekacin population pharmacokinetic models to Japanese pediatric patients for evaluation of dosing regimen based on Japanese TDM guidelines
Background: Arbekacin (ABK) is an effective aminoglycoside antibiotic agent against methicillin-resistant Staphylococcus aureus (MRSA) used with the recommendation of therapeutic drug monitoring (TDM) in Japanese clinical practice guidelines for TDM1). Since differences in age and body weight (BW) can affect ABK pharmacokinetics (PK), empirical Bayesian methods using population PK (PPK) models with age and/or BW […]
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 […]
Optimising Inductive Linearisation for nonlinear ODEs with an application to the Michaelis-Menten model: a stochastic simulation-estimation study
Background: Solving systems of nonlinear differential equations is of significant interest in applying pharmacokinetic-pharmacodynamic and systems pharmacology. Inductive Linearisation (IndLin) [1] is a numerical solver that has been developed for generating approximated solutions to nonlinear systems based on iterative linearisation to yield a linear time-varying (LTV) ODE. The method is then paired with the integrator […]
A model for procalcitonin concentrations following birth in non infected preterm neonates
Background: Procalcitonin (PCT) may be used to monitor infection and guide antibiotic therapy (1). However its usefulness in neonates is hampered due to changes following birth and events such as surgery. Methods: PCT concentrations measured in 282 non-infected pre-term and term neonates (22 and 41 weeks gestation) were provided for analysis (2). A turnover model was […]
PBPK Modeling of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Binding, pH-dependent Solubility and Nonsink Permeation
Introduction: Vismodegib displays unique pharmacokinetic characteristics including saturable plasma protein binding to alpha-1 acid glycoprotein (AAG) and apparent time-dependent bioavailability leading to non-linear PK with dose and time, significantly faster time to steady-state and lower than predicted accumulation. Objectives: Given these unique characteristics, a PBPK model was developed to explore mechanistic insights into saturable protein […]
Matters close to the heart: adaptation of tacrolimus models to inform therapeutic drug monitoring using the PRIOR approach
Introduction. External evaluation of published tacrolimus population pharmacokinetic models (n=17) highlighted that no available model accurately describes tacrolimus disposition in heart transplant (HTX) recipients, both with and without concomitant azole antifungal therapy.1 Concomitant azole antifungal therapy alters tacrolimus disposition substantially necessitating dose adjustments. The incorporation of azole antifungal use as a covariate may improve model-predicted […]
An ex vivo study measuring antibiotic adsorption to cardiopulmonary bypass circuitry
Background: Cephazolin and vancomycin are commonly used for antibiotic prophylaxis during surgery supported by cardiopulmonary bypass (CPB). Antibiotic pharmacokinetics (PK) can be altered by CPB through haemodilution, haemofiltration, hypothermia and drug adsorption to the circuitry (1). Adsorption can contribute to decreased antibiotic concentrations with consequent reduced prophylactic effectiveness (2). Highly protein bound drugs like cephazolin […]
Saliva for TDM of antifungal drugs: voriconazole model
Aims. Therapeutic drug monitoring (TDM) is recommended for many antifungal drugs. Saliva sampling is a non-invasive alternative to plasma sampling. However, no clinically validated saliva models available. This study firstly aims to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to […]
A mathematical model of CB1 receptor allosteric modulation
Introduction: The type 1 cannabinoid receptor (CB1) is among the most abundant G-protein coupled receptors in the central nervous system. CB1 modulates neurotransmission, and plays a vital role in both physiology and pathology. Allosteric ligands bind to a different site on the receptor to the endogenous (orthosteric) ligand and can have effects that are unique […]