Population pharmacokinetics of itraconazole

Itraconazole is a triazole antifungal used in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF) and for the prevention of invasive fungal infections in paediatric patients undergoing bone marrow transplants (BMT). The pharmacokinetic (PK) properties of this drug and its active metabolite have been described before; however, there is only sparse information available of the PK properties of this drug in the general paediatric population and CF patients in particular. Even though the target concentrations to obtain treatment success from this drug in ABPA have not been established, therapeutic drug monitoring has been shown to be necessary due to a high interpatient variability and low concentrations reported in these patient groups. The general aim of this thesis was to use modelling approaches to provide a better understanding of the PK of itraconazole, in particular to investigate the relative bioavailability of the two commercial formulations (capsule and oral solution), and to attempt to evaluate relationships between patient characteristics and parameters to enable better individualised therapy to maximise the benefits of this drug. The first study was a paediatric population PK (popPK) investigation of itraconazole and its active metabolite hydroxy-itraconazole in CF and BMT patients. All paediatric CF or BMT patients taking oral itraconazole for therapeutic reasons were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. Itraconazole and hydroxy-itraconazole plasma concentrations were measured by a newly developed and validated high-performance liquid chromatography. A nonlinear mixed-effects modelling approach (NONMEM 5.1.1) was used to describe the PK of itraconazole and hydroxy-itraconazole simultaneously. A 1-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order conversion to hydroxy-itraconazole. For itraconazole, the apparent clearance and volume of distribution was 35.5 L/h and 672 L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h¯¹ and for the oral solution formulation it was 0.959 h¯&sup1. The relative bioavailability for the capsules was 0.55. Of several screened covariates, only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. High inter-patient variability confirmed previous data in CF, leukaemia and BMT patients. From the population model, simulations were performed to develop more adequate dosage regimens to achieve target therapeutic trough plasma concentration of 0.5 mg/L. Higher doses of itraconazole than presently used are needed in these patients, particularly when it is prescribed as capsules. To further support the aims of the thesis, a popPK study with oral itraconazole and its active metabolite in adult patients with CF for capsule and oral solution was performed. A D-optimal study design was developed in MATLAB using POPT v. 2.0, B, which was based on the administration of solution and capsules to 30 patients in a cross-over design. Eight blood samples were taken on two occasions as per the optimal sampling design and assayed by HPLC. NONMEM (5.1.1) was used for the popPK analysis. A total of 241 blood samples were collected, of which 94% were taken within the defined optimal sampling window. A 2-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order formation for metabolism to the hydroxy-metabolite. Absorption rate constants for capsule and solution were 0.0315 h¯¹ and 0.125 h¯¹, respectively. The comparative bioavailability of the capsule to solution was 0.82 in this study. There was no evidence of nonlinearity in the PK of itraconazole and no screened covariate significantly improved the fit to the data. There was high inter-patient variability confirmed previous results in CF. The optimal design performed well for estimation of model parameters from a complex parent-metabolite popPK model. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but at times that were “near-optimal” for estimating the popPK parameters. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily would provide a trough target concentration at steady state in only 35% of patients when administered as the solution, and 31% when administered as the capsules. The optimal dosing schedule was 500 mg b.d. for both formulations. Since the therapeutic target for itraconazole, is still unresolved, the potential risks of these dosing schedules need to be assessed on an individual basis. This thesis provides information on several methods and their applications to sparse sampling population pharmacokinetic studies and offers results and future directions to maximize the benefits of itraconazole therapy. The population modelling approach has been successfully applied to both clinical studies