Clinical pharmacokinetics and dose recommendations for posaconazole gastro-resistant tablets in children with Cystic Fibrosis
File(s)
Published version
Author(s)
Bentley, sian
Davies, Jane
Gastine, Silke
Donovan, Jackie
Standing, Joseph F
Type
Journal Article
Abstract
Objectives
To investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses.
Patients and methods
Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function.
Results
One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients.
Conclusions
A starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L.
To investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses.
Patients and methods
Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function.
Results
One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients.
Conclusions
A starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L.
Date Issued
2021-12
Date Acceptance
2021-07-21
Citation
Journal of Antimicrobial Chemotherapy, 2021, 76 (12), pp.3247-3254
ISSN
0305-7453
Publisher
Oxford University Press
Start Page
3247
End Page
3254
Journal / Book Title
Journal of Antimicrobial Chemotherapy
Volume
76
Issue
12
Copyright Statement
© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://academic.oup.com/jac/article/76/12/3247/6359520
Subjects
Microbiology
0605 Microbiology
1108 Medical Microbiology
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2021-08-30