Hugh Miller

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

AbstractObjective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients.n Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children’s Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. Itraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite.n Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (Vd(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h−1 and for the oral solution formulation was 0.96 h−1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (Frel) was 0.55. For the metabolite, volume of distribution, Vm/(F · fm), and clearance, CL/(F · fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazole/F and Vd(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazole/F, Vd(itraconazole)/F, CLm/(F · fm) and Frel, respectively. The correlation between random effects of CLitraconazole and Vd(itraconazole) was 0.69.n Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof‐of‐concept study

AIMnThe aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour.nnnMETHODSnThis was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48u2009h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) u2009weeks gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety.nnnRESULTSnUterine quiescence was achieved in 62% of women who received retosiban (nu2009=u200930) compared with 41% who received placebo (nu2009=u200934). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2u2009days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7u2009days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups.nnnCONCLUSIONSnIntravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Characteristics of adverse medication events in a children's hospital.

To compare adverse medication events (AMEs) reported in children, via the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD‐10) coding with events reported via other data sources.

A national study of the processes and outcomes of paediatric formulary applications in Australia.

Objective: To evaluate the processes by which pharmaceuticals are added to the formularies of Australian paediatric hospitals.