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Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous(More)
We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading(More)
AIMS To describe the population pharmacokinetic-pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. METHODS A total(More)
BACKGROUND QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT(More)
AIMS A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored. METHODS Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33(More)
AIMS To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies. METHODS A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of(More)
The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of(More)
To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC. Tumor size (TS) data were modeled(More)
AIM If appropriately accounted for in a pharmacokinetic (PK)-pharmacodynamic (PD) model, time-varying covariates can provide additional information to that obtained from time-constant covariates. The aim was to present and apply two models applicable to time-varying covariates that capture such additional information. METHODS The first model estimates(More)
A randomised crossover study was performed in subjects with rheumatoid arthritis (or other arthropathies) to investigate if any alteration in the steady pharmacokinetics of the NSAID piroxicam (a drug which is extensively metabolised via cytochrome P450) or its major metabolites occurred as a result of coadministering either cimetidine or nizatidine. Twelve(More)