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Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients.
Clin Pharmacokinet. 2006; 45(11):1099-114.CP

Abstract

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.

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.

Authors+Show Affiliations

School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australian. s.hennig@pharmacy.uq.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

17048974

Citation

Hennig, Stefanie, et al. "Population Pharmacokinetics of Itraconazole and Its Active Metabolite Hydroxy-itraconazole in Paediatric Cystic Fibrosis and Bone Marrow Transplant Patients." Clinical Pharmacokinetics, vol. 45, no. 11, 2006, pp. 1099-114.
Hennig S, Wainwright CE, Bell SC, et al. Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients. Clin Pharmacokinet. 2006;45(11):1099-114.
Hennig, S., Wainwright, C. E., Bell, S. C., Miller, H., Friberg, L. E., & Charles, B. G. (2006). Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients. Clinical Pharmacokinetics, 45(11), 1099-114.
Hennig S, et al. Population Pharmacokinetics of Itraconazole and Its Active Metabolite Hydroxy-itraconazole in Paediatric Cystic Fibrosis and Bone Marrow Transplant Patients. Clin Pharmacokinet. 2006;45(11):1099-114. PubMed PMID: 17048974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients. AU - Hennig,Stefanie, AU - Wainwright,Claire E, AU - Bell,Scott C, AU - Miller,Hugh, AU - Friberg,Lena E, AU - Charles,Bruce G, PY - 2006/10/20/pubmed PY - 2007/1/6/medline PY - 2006/10/20/entrez SP - 1099 EP - 114 JF - Clinical pharmacokinetics JO - Clin Pharmacokinet VL - 45 IS - 11 N2 - 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. 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. SN - 0312-5963 UR - https://www.unboundmedicine.com/medline/citation/17048974/Population_pharmacokinetics_of_itraconazole_and_its_active_metabolite_hydroxy_itraconazole_in_paediatric_cystic_fibrosis_and_bone_marrow_transplant_patients_ L2 - https://dx.doi.org/10.2165/00003088-200645110-00004 DB - PRIME DP - Unbound Medicine ER -