Population pharmacokinetics of unbound voriconazole following two different routes of administration during sequence therapy
Franziska Kluwe (1,2), Claudia Kirbs (1,3), Lisa Ehmann (1,2), Franziska Drescher (3), Peter Matzneller (4), Wilhelm Huisinga (5), Markus Zeitlinger (4), Charlotte Kloft (1)
(1) Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Graduate Research Training Program PharMetrX, Germany, (3) Department of Clinical Pharmacy, Institute of Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, Germany, (4) Department of Clinical Pharmacology, Medical University of Vienna, Austria, (5) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives: Voriconazole (VRC), a broad-spectrum antifungal drug used to treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by CYP isoenzyme 2C19 [1]. The aim of the current work was to investigate the pharmacokinetics of VRC after standard sequence dosing in healthy volunteers in plasma.
Methods: A prospective, open-labelled, uncontrolled study was conducted in collaboration with the Medical University of Vienna. 10 healthy male individuals (age: 21-46 years, weight: 65-83 kg) received the standard dosing regimen for VRC of initially short-term i.v. infusions and subsequently p.o. administrations every 12 hours (2x6 mg/kg i.v., 2x4 mg/kg i.v., 3x200 mg p.o.). Intensive plasma sampling was carried out over 4 days and the unbound VRC concentrations were determined by high-performance liquid chromatography [2]. Data analysis and modelling activities were performed using R (3.3.2) and NONMEM (7.3.0) with first-order conditional estimation method and interaction option. To assess the model performance, graphical model evaluation techniques, such as goodness-of-fit plots were used.
Results: High variability in the VRC concentrations was shown and increased with the number of VRC doses administered. A two-compartment model with zero-order input (i.v) and first-order absorption (p.o) was suitable to describe the pharmacokinetics of unbound VRC in healthy volunteers. Oral bioavailability was fixed to a published value [3]. VRC clearance (CL) was estimated to be 14.4 L/h, central volume of distribution (Vc) 161.0 L, intercompartmental clearance (Q) 71.9 L/h, peripheral volume of distribution (Vp) 603.0 L and absorption rate constant (ka) 2.21 h-1. Interindividual variability implemented on CL, Vc, Vp, Q and ka and using an exponential model was highest for CL (84.4 CV%).
Conclusions: The developed model adequately described the pharmacokinetics of unbound VRC in plasma and despite standard dosing in healthy volunteers identified substantial interindividual variability in clearance. The model performance was better for the initial i.v. phase of the sequence therapy, i.e. time- and/or concentration- and/or formulation-dependent pharmacokinetics will be further investigated. Next, a covariate analysis will be performed to identify factors (e.g. CYP2C19 genotype) explaining the high pharmacokinetic variability.
References:
[1] G. Mikus, I.M. Scholz, J. Weiss. Pharmacogenomics of the triazole antifungal agent voriconazole. Pharmacogenomics, 12: 861–872 (2011).
[2] F. Simmel, J. Soukup, A. Zoerner, et al. Development and validation of an efficient HPLC method for quantification of voriconazole in plasma and microdialysate reflecting an important target site. Anal. Bioanal. Chem., 392: 479–488 (2008).
[3] European Medicines Agency. European public assessment reports: VFEND. [cited 2017 Feb 25]: 1–154 (2012).