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 […]
Abstracts
A Population Approach to Evaluate the Parent-Metabolite Pharmacokinetics of a Novel Oral SN38 Prodrug in Rats
Background: Irinotecan hydrochloride and its active metabolite (SN38) function as topoisomerase I inhibitors, with the active metabolite being 100-1000 times more potent. Although irinotecan is widely used as a first-line therapy in metastatic colorectal cancer (mCRC), significant interindividual pharmacokinetic (PK) variability and dose-limiting toxicities restrict its application. We have developed a novel lipid-drug conjugate of […]
Pharmacokinetics of tobramycin in children with cystic fibrosis
Introduction: Cystic fibrosis (CF) is a genetic condition characterised by severe lung disease often requiring frequent hospital admissions for pulmonary exacerbations requiring intravenous antibiotic treatment. Tobramycin, an aminoglycoside antibiotic, is commonly used to treat pulmonary exacerbations in those with Pseudomonas aeruginosa infections; however, it is unknown whether current paediatric dosing regimens achieve safe and effective […]
Using transduction models to describe the time-course of extracellular metabolites in a hollow-fibre infection model
Background Extracellular bacterial metabolites have potential as markers of bacterial growth and resistance emergence, but have not been evaluated in dynamic in vitro studies. Aim To mathematically describe the relationship between bacterial response and extracellular metabolites in a HFIM. Methods An MDR hypermutable Pseudomonas aeruginosa CF clinical isolate was challenged with ceftolozane-tazobactam (C/T) simulating continuous […]
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 […]
A population pharmacokinetic model of SC insulin therapy for hyperglycemia during acute ischemic stroke among patients with pre-existing diabetes
Background: Regardless of pre-stroke diabetes status, patients admitted to the hospital for acute ischemic stroke are frequently observed to have elevated levels of blood glucose or hyperglycemia[1]. Hyperglycemia is associated with poor stroke outcomes[2]. Insulin therapy to achieve normoglycemia during the acute phase is associated with better clinical outcomes in other groups of critically ill […]
Mechanistic Modelling of Gastric pH-Dependent Drug-Drug Interactions
Co-administration of acid reducing agents (ARAs) with drugs exhibiting pH-dependent solubility can lead to drug-drug interactions mediated by gastric pH changes (pH-dependent DDIs). Physiologically based pharmacokinetic (PBPK) modelling is recognized by the U.S. FDA as an alternative approach to clinical trials for the evaluation of pH-dependent DDIs1. To date, such DDIs have predominantly been assessed […]
The identifiability of a turnover model for allopurinol urate-lowering effect-
Introduction. Allopurinol is used for the treatment of gout. The primary physiological response to allopurinol therapy is a reduction in serum urate concentrations. Attempts to model the pharmacokinetics and pharmacodynamics (PK & PD) of allopurinol using a turnover model have consistently produced unstable models with imprecise and biased estimates for some PD parameters (e.g. Kout) […]
Population Pharmacokinetic Parent-Metabolite Modeling of Tenofovir Alafenamide in Healthy Korean Volunteers
Background: Tenofovir alafenamide (TAF) is widely used drug as a first-line drug for managing hepatitis B virus infection. TAF was developed as the prodrug of tenofovir (TFV) to decrease renal and bone toxicities through lower dose administration and sufficient systemic exposures than other salt forms of TFV. TAF is also a highly variable drug in […]
Favipiravir pharmacokinetics in infants and young children with chronic RNA viral infections
Background Favipiravir selectively inhibits RNA polymerase responsible for single-stranded viral replication. It is licensed for treating influenza and repurposed to treat other diseases such as Ebola1 and COVID-192. It is metabolised by hepatic aldehyde oxidase (AO) and is an AO inhibitor with complex pharmacokinetics. AO expression is shown to rapidly increase in first two years […]