Background: Assessment of goodness of fit of a model to the data set is essential to ensure the model provides a reasonable description of the events seen. For logistic regression the most common diagnostic used for this purpose is binning the data and comparing the empirical probability of an event in each bin to the model […]
Abstracts
Understanding intranasal fentanyl for acute pain treatment in children: randomized controlled trials or population pharmacodynamic studies?
Introduction: The use of intranasal fentanyl for pain relief in children’s emergency departments is gaining popularity following the publication of a randomised controlled trial showing intranasal fentanyl to be as effective as intravenous morphine while being easier to administer1. Unfortunately, intranasal fentanyl is being used with younger children, higher doses, and with a different formulation to […]
Does the use of Lean Body Weight (LBW) in a modified Cockcroft-Gault (C-G) equation provide a better prediction of gentamicin clearance?
Background: The Cockcroft and Gault (C-G) method of calculating creatinine clearance (CLcr) does not appear to perform well at low concentrations of serum creatinine and the extremes of body sizes. Aim: To evaluate the performance of a modified C-G equation to predict gentamicin clearance. Methods: Demographics and gentamicin pharmacokinetic parameters were collected from 999 subjects as part of […]
The Effect of Study Design on Pharmacokinetics in Patients with Impaired Renal Function
Backgroud: To ensure the effect of renal function on drug exposure is precisely quantified, FDA guidance1recommends that studies recruit approximately equal subject numbers with normal renal function and mild, moderate and severe renal impairment. However, in population PK analyses it is common to pool data from various studies, resulting in an over-representation of subjects with normal […]
A nonlinear mixed effects model to characterise lamivudine absorption and distribution
Background: Lamivudine (3TC), a potent selective inhibitor of HIV reverse transcriptase, is used in combination antiretroviral therapy (ART). 3TC pharmacokinetics is characterised by highly variable absorption and is rapidly distributed to a slow equilibrating peripheral compartment. Although not considered a candidate for routine therapeutic drug monitoring, 3TC pharmacokinetics is unaltered by concomitant anti-tuberculosis treatment, a […]
Risk of QTc Interval Prolongation and Torsades de Pointes (TdP) with Amisulpride
Background: Amisulpride has been associated with Torsades de Pointes (TdP) after overdose. But the precise relationship between amisulpride dose, QTc interval prolongation and TdP is unknown. Aim: To evaluate the dose response relationship of amisulpride for causing QTc interval prolongation and TdP. Methods: QT intervals were measured from 196 ECGs for 41 patients (23 males […]
The Influence of Study Design on Identification of True Parameter-Covariate Relationships
Background: Utilisation of D-optimality together with clinical trial simulation are currently the primary methods used to inform clinical trial study designs and facilitate precise estimation of pharmacokinetic-pharmacodynamic (PK-PD) model parameters. A recent simulation study has extended the application of these methods to the qualitative identification of correct covariates [1]. However, the authors did not investigate the […]
Correlation in the absorption of lamivudine and zidovudine when administered as a fixed-dose combination tablet
Background: Lamivudine (3TC) and zidovudine (AZT) are potent selective inhibitors of HIV reverse transcriptase and, due to their synergistic effect, are available as a fixed dose combination (FDC) tablet for use in antiretroviral therapy (ART). The absorption and exposure of AZT and 3TC from single component and fixed-dose combination formulations are considered to be comparable. […]
Population pharmacokinetics of mycophenolic acid in children and young people undergoing bone marrow and solid organ transplantation
Background: Mycophenolate mofetil (MMF) is used as an immunosuppressant for the treatment and prevention of graft-versus host disease (GVHD) in bone marrow transplantation (Nash et al 2005) and acute graft rejection in solid organ transplantation (Srinivas et al 2003). Mycophenolic acid (MPA) is the active metabolite of MMF. MPA displays variability in treatment response which supports the need for individualised […]
Robust D-optimal Design of Nonlinear Fixed Effects Pharmacokinetic Model
Background: D-optimality is often used to design an optimum experiment for the purpose of parameter estimation. When the model is nonlinear, D-optimal designs depend on the nominal parameter values in the model, which are unknown. In order to address this dependency issue, various robust optimal design methods have been introduced [1, 2]. These methods utilize prior […]