Tag Archives | 2021

Extrapolating pharmacokinetic models from adults to neonates and infants: Case studies with paracetamol

The absorption, distribution, metabolism and excretion (ADME) of drugs in the human body may be quite different between adults and infants/neonates, since the enzymes involved in metabolic pathways exhibit distinct levels of activities at different ages. In the case of paracetamol, for example, neonates have a lower total clearance per kg bodyweight compared with adults, […]

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QSP Model Simplification Using Machine Learning with an Application to Heparin Dose-Response in Children

Introduction The coagulation network model is used to describe the relationship between an anticoagulant, or pro-coagulant, and a clotting test outcome [1]. The system consists of an in-vivo (62 ODEs and 184 parameters) and in-vitro (62 ODEs and 182 parameters) modules. These two modules are linked by a discontinuous interface with the whole function not being […]

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Investigating myotoxicity following red-bellied black snake envenomation

Background: Red-bellied black snake (RBBS; Pseudechis porphyriacus) envenomation can cause systemic myotoxicity, which is characterised by elevated serum creatine kinase (CK) concentrations greater than 1,000 U/L. An understanding of the time course of venom concentrations and serum CK is useful for developing treatment plans for envenomed patients. Aims: This study aims to 1) determine whether […]

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Physiologically-based pharmacokinetic (PBPK) models for translation of drug distribution from rat to human

Background: Optimization of drug specific parameters in complex models, such as whole body physiologically-based pharmacokinetic (WBPBPK) models, by model fitting to observed data is challenging. This process is time-consuming and models are often unidentifiable/over-parameterized due to the large number of parameters and availability of data which are mostly limited to observations from plasma [1]. The […]

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A quantitative systems pharmacology model for paracetamol overdose and rescue

Introduction: Paracetamol toxicity is the leading cause of acute liver failure in many countries. The most commonly discussed mechanism for paracetamol poisoning is the production of the highly reactive toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI can deplete liver glutathione (GSH) and bind with liver protein and cause liver injury with higher doses of paracetamol. Among […]

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A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability %) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) […]

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Issues with virtual populations when applied to nonlinear QSP models

Introduction Quantitative systems pharmacology (QSP) models describe the clinical pharmacological properties of a drug.  They are typically described as systems of linear mass-balance and nonlinear mass-action of drugs.  One of the purposes of QSP models is to simulate potential outcomes from virtual clinical trials. This approach is predicated on generating virtual populations of patients (a […]

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Toward an in silico viral kinetic model for Covid-19 with pharmacodynamic effects

Viral kinetics models have been successfully developed for infection diseases such as influenza A. The aim of this work is to adopt the rationale for the viral kinetics of SARS-CoV-2, while incorporating pharmacodynamic effects of Remdesivir, the only FDA-approved drug for Covid-19 at this stage. The model consists of a system of differential equations where […]

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Population pharmacokinetics of dimethylacetamide in children receiving intravenous busulphan

Introduction: Administration of high-dose busulphan is a critical component in many conditioning regimens for both adults and children before haemopoietic stem cell transplantation. Current intravenous formulations of busulphan contain N,N-dimethylacetamide (DMA), which is an organic solvent that acts as an excipient for drug administration. Despite available information regarding the safety of DMA use in myeloablative […]

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Implementation of a physiologically-based pharmacokinetic modelling approach to evaluate inter-ethnic differences in imatinib dosing regimens

Background This study implements a PBPK modelling approach to investigate inter-ethnic differences in imatinib dosing regimens. Methods A PBPK model of imatinib was built in the Simcyp Simulator (v.17) integrating in vitro metabolism and clinical pharmacokinetic data and accounting for ethnic differences in body size and expression of CYP enzymes and proteins involved in imatinib […]

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