Article date: April 2007
By: Stefanie Hennig, Timothy H. Waterhouse, Scott C. Bell, Megan France, Claire E. Wainwright, Hugh Miller, Bruce G. Charles, Stephen B. Duffull, in Volume 63, Issue 4, pages 438-450
What is already known about this subject
• Itraconazole is a triazole antifungal used in the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis (CF).
What this study adds
• This study reports for the first time the population pharmacokinetic properties of itraconazole and a known active metabolite, hydroxy‐itraconazole in adult patients with CF.
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.
DOI: 10.1111/j.1365-2125.2006.02778.x
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