Background: When performing a population pharmacokinetic (PK) modeling analysis covariates, such as weight, gender etc. might be included into the model to explain part of the parameter variability. Parameter variability can be defined as the sum of unexplained (random) parameter variability (UPV) and explained (predictable) parameter variability (EPV). If inclusion of a covariate on a […]
2012
Pharmacokinetics of high-dose methotrexate in children with cancer: A mechanism-based evaluation of clearance prediction
Background High-dose methotrexate (HDMTX) represents an important treatment modality in several pediatric cancers, though managing toxicities with HDMTX continues to be a challenge. Due to its narrow therapeutic window as well as significant variability in its pharmacokinetics, the current management of the MTX therapy is complicated. Urine alkalinization, vigorous hydration, and rescue with leucovorin are […]
A clinical trial incident: Why simple PK is sometimes not so simple
The antibiotic dose calculator trial in children aims to find out if a web based dose calculator is better than department protocols used in 3 clinical units for achieving target concentrations of amikacin, gentamicin or vancomycin. During the trial an incident occurred when the dose calculator dose proposed a clearly inappropriate maintenance dose and dosing […]
Prediction correction: quick fix for VPC misdiagnosis in a tacrolimus popPK model
After spending weeks on modelling with little progress it occurred to us that the problem might lie with the diagnostic – not the model. Background: A VPC (visual predictive check) is a graphically representation of multiple simulations of a model. Percentiles of both the observed and the simulated data are plotted against an independent variable […]
What is the between cycle variability in methotrexate clearance?
Background High dose methotrexate (MTX) is the mainstay of treatment for many cancers. It is typically administered on repeated occasions known as ‘cycles’. Due to extensive variability in its pharmacokinetics (PK) and life-threatening toxicity, the use of repeated MTX concentration measurements to determine the duration of leucovorin dosing has decreased the incidence of severe toxicity. […]
NextDose – A web based collaborative tool for dose individualisation
A web based collaborative tool has been developed for helping with dose individualisation. It has been applied to dosing busulphan for conditioning prior to marrow transplantation. NextDose stores patient information seperately from the web interface for security. This information is stored in a non-identifiable format and requires authorised use of the NextDose application to combine […]
A model for fat free mass in humans from very premature neonates to young adults
Objectives: To describe the maturation of fat free mass (FFM) from prematurity to adulthood as a function of postmenstrual age (PMA) using nonlinear mixed effect modeling. Background: A model for FFM for adults has been well described, with different formulae for males and females (1). An extension to this model using data from age 3 […]
The pharmacokinetic profile of intravenous paracetamol in adult patients undergoing major abdominal surgery: A population analysis
The aim of the present study was to determine the effect of major surgery on paracetamol glucuronidation and sulfation. 53 patients were given doses of either 1, 1.5 or 2 g of paracetamol by intravenous (IV) infusion. A combination of rich and sparse plasma and urine samples were collected over a 7 day period (Day […]
Adaptive PD-optimal design of a pilot study for a clotting time test for enoxaparin
Background: Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. There is no standard measure of enoxaparin clinical effectiveness. We recently showed that a Xa clotting time test could potentially assess the effect of enoxaparin on the clotting system [1]. Preliminary in […]
Evaluation of a Bayesian dose-individualisation method for enoxaparin
Background: Enoxaparin is a low molecular weight heparin used in the treatment of thrombosis. The current approved treatment dose of enoxaparin is based on total body weight and its dosing frequency is based dichotomously on creatinine clearance. Recent evidence has shown these dosing strategies to be suboptimal and Bayesian dose-individualisation has been proposed as a […]