Background: Sodium nitroprusside (SNP) is commonly used to control blood pressure (BP) in children during surgery. Recently, the results from a clinical trial in children using SNP during surgery were used to develop a KPD model to help guide the dosing of SNP in this population. [1] The model revealed that there were two subpopulations of […]
2019
PKPD Explorations Using Paracetamol; 20 years on
Paracetamol (acetaminophen) has served as a useful substrate for population modelling and factors determining dose. This modelling has improved not only PKPD understanding of the drug, but has also been useful to explore models that characterize size (e.g., allometry), clearance maturation, the impact of birth on clearance, the role of fat mass, concentration-response relationships, delayed […]
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 […]
Pharmacometric modelling of deuterium exposure in breastfeeding mother-infant pairs for the determination of exclusive breastfeeding practice
Background: The World Health Organization (WHO) recommends exclusive breastfeeding (EBF) for the first 6 months after birth. A stable isotope deuterium dose-to-mother (DTM) technique can be used to determine whether an infant is EBF by estimating quantitatively the intake of breastmilk and non-breastmilk water intake. This method has several advantages as it is non-invasive, simple to […]
Investigating the pharmacokinetics of snake venom – a cocktail of toxins
Background: Snake venom is a mixture of protein-toxins, which can cause a range of biological effects. The protein components in snake venom have molecular sizes ranging from 4 kDa to 150 kDa and are expected to exhibit different pharmacokinetics (PK) profiles. Therefore, the phenomenological appearance of plasma snake venom concentrations is governed by the combination of […]
A mathematical model for warfarin reversal using vitamin K
Introduction: Vitamin K is indicated for warfarin reversal when active bleeding is present or when there is a high risk of bleeding (INR > 5). However, choosing an appropriate dose of vitamin K is challenging due to our limited understanding of the dose-response relationship and the interactions between warfarin and the vitamin K cycle. For instance, […]
A quantitative systems pharmacology model for glutathione depletion during paracetamol overdose
Introduction: Paracetamol toxicity is a common cause of acute liver failure in many countries. Most paracetamol is metabolised to the non-toxic sulfate and glucuronide conjugates. Only about 5% is oxidised to the highly reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by hepatic glutathione(GSH). At higher doses of paracetamol, NAPQI depletes stores of both GSH and cysteine. […]
An extension of Janmahasatian’s fat-free mass model to incorporate differences due to ethnicity
Introduction: Janmahasatian’s [1] model for fat-free mass model (FFMJan) was developed based on a population that descended from European ancestry. There is some evidence that humans from different ethnic backgrounds may have different body composition based on standard phenotypic characteristics (e.g. sex, weight and height) and hence the model may not predict well into these groups. In […]
Dose banding- weighing up benefits vs risks
Background: Dose banding is the allocation of patients into a pre-specified dose group based on the patient’s value of a covariate and is commonly recommended in drug labels. The simplest form of dose banding assigns all patients to receive the same dose irrespective of their characteristics. The corollary to “one dose fits all” is where […]