Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients.
OBJECTIVE
The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxy-itraconazole 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.


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.


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 (CL(itraconazole)) was 35.5 L/hour, the apparent volume of distribution (V(d(itraconazole)) was 672 L, 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 (F(rel)) was 0.55. For the metabolite, volume of distribution, V(m)/(F . f(m)), and clearance, CL/(F . f(m)), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CL(itraconazole)/F and V(d(itraconazole))/F (standardised to a 70 kg person) using allometric three-quarter power scaling on CL(itraconazole)/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 CL(itraconazole)/F, V(d)((itraconazole)())/F, CL(m)/(F . f(m)) and F(rel), respectively. The correlation between random effects of CL(itraconazole) and V(d(itraconazole)) was 0.69.


CONCLUSIONS
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.
Hennig
Stefanie
S
School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australian. s.hennig@pharmacy.uq.edu.au
Wainwright
Claire E
CE
Bell
Scott C
SC
Miller
Hugh
H
Friberg
Lena E
LE
Charles
Bruce G
BG
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000097:blood / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D017964:Itraconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D011159:Population Surveillance; D015203:Reproducibility of Results
D000935:Antifungal Agents; C084794:hydroxyitraconazole; D017964:Itraconazole