Ad‐optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients

Abstract

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). • The pharmacokinetic (PK) properties of this drug and its active metabolite have been described before, mostly in healthy volunteers. • However, only sparse information from case reports were available of the PK properties of this drug in CF patients at the start of our study. 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. • As a result, this study offers new dosing approaches and their pharmacoeconomic impact as well as a PK model for therapeutic drug monitoring of this drug in this patient group. • Furthermore, it is an example of a successful d‐optimal design application in a clinical setting. 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.

Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children

“…Increasing from 100 to 200 mg decreases the bioavailability by 40%, whereas increasing from 200 to 400 mg decreases the bioavailability by almost half, explaining the marginal increases in trough concentration with increasing doses. In common with findings for itraconazole [43], increasing the frequency is more successful, but dose administrations of greater than four times per day are simply impractical.…”

Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

“…Population pharmacokinetic models of itraconazole kinetics in the literature to date have used linear elimination kinetics (35)(36)(37)(38)(39)(40). Linear itraconazole kinetics was also found for the model of single-dose data developed in this analysis, but this model underpredicted multidose concentrations, suggesting a deviation from the assumption of linearity outside the single-dose setting.…”

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

“…Therefore, therapeutic drug monitoring has been recommended [73]. These problems are exaggerated in patients with CF as compared with asthma and, therefore, higher doses of itraconazole capsule or use of the cyclodextrin liquid formulation have been recommended for CF patients [74][75][76]. It may be difficult to achieve optimal efficacy with itraconazole in CF patients.…”