A D-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients

Hennig, Stefanie, Waterhouse, Timothy H., Bell, Scott C., France, Megan, Wainwright, Claire E., Miller, Hugh, Charles, Bruce G. and Duffull, Stephen B. (2007) A D-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients. British Journal of Clinical Pharmacology, 63 4: 438-450.


Author Hennig, Stefanie
Waterhouse, Timothy H.
Bell, Scott C.
France, Megan
Wainwright, Claire E.
Miller, Hugh
Charles, Bruce G.
Duffull, Stephen B.
Title A D-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients
Journal name British Journal of Clinical Pharmacology  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2007-04
Sub-type Article
Year available 2006
DOI 10.1111/j.1365-2125.2006.02778.x
Volume number 63
Issue number 4
ISSN 0306-5251
Start page 438
End page 450
Total pages 13
Editor E. J. Begg
J. M. Ritter
M. S. Lennard
Place of publication United Kingdom
Publisher Blackwell
Collection year 2007
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730101 Infectious diseases
730110 Respiratory system and diseases (incl. asthma)
Abstract Aim The primary objective of the study was to estimate the population pharmacokinetic parameters for itraconazole and hydroxy-itraconazole, in particular, the relative oral bioavailability of the capsule compared with solution in adult cystic fibrosis patients, in order to develop new dosing guidelines. A secondary objective was to evaluate the performance of a population optimal design. Methods The blood sampling times for the population study were optimized previously using POPT v.2.0. The design was based on the administration of solution and capsules to 30 patients in a cross-over study. Prior information suggested that itraconazole is generally well described by a two-compartment disposition model with either linear or saturable elimination. The pharmacokinetics of itraconazole and the metabolite were modelled simultaneously using NONMEM. Dosing schedules were simulated to assess their ability to achieve a trough target concentration of 0.5 mg ml(-1). Results Out of 241 blood samples, 94% were taken within the defined optimal sampling windows. A two-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order metabolism to the hydroxy-metabolite. For itraconazole the absorption rate constants (between-subject variability) for capsule and solution were 0.0315 h(-1) (91.9%) and 0.125 h(-1) (106.3%), respectively, and the relative bioavailability of the capsule was 0.82 (62.3%) (confidence interval 0.36, 1.97), compared with the solution. There was no evidence of nonlinearity. Simulations from the final model showed that a dosing schedule of 500 mg twice daily for both formulations provided the highest chance of target success. Conclusion The optimal design performed well and the pharmacokinetics of itraconazole and hydroxy-itraconazole were described adequately by the model. The relative bioavailability for itraconazole capsules was 82% compared with the solution.
Keyword Pharmacology & Pharmacy
cystic fibrosis
itraconazole
optimal design
population pharmacokinetics
Allergic Bronchopulmonary Aspergillosis
Steady-state Pharmacokinetics
Parameter-estimation
Healthy-volunteers
Food Interaction
Capsules
Therapy
Model
Optimization
Prophylaxis
Q-Index Code C1

 
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