Blood and tissue distribution of posaconazole in a rat model of invasive pulmonary aspergillosis

Abstract

Posaconazole is the recommended prophylactic agent in patients at high risk of invasive fungal infection, since adequate drug levels seem to be reached in target sites despite the relatively low levels detected in blood. The objective of this study is to obtain pharmacokinetic (PK) information associated to blood and tissue distribution of posaconazole in an animal model of invasive pulmonary aspergillosis. The PK parameters in lung samples were systematically higher than in serum. After multiple-dose administration of posaconazole, a significant accumulation of the drug was evident in lung tissue. The PK behavior of posaconazole in this particular experimental model is similar to that observed in humans. Thus, we believe this model could be a valid tool to evaluate posaconazole exposure–response relationship.

Introduction

Invasive aspergillosis remains a major cause of morbidity and mortality, particularly among immunocompromised patients (Chandrasekar, 2009). Management of these infections includes early treatment and administration of the appropriate antifungal agent at the appropriate dosage.

Posaconazole is a triazole antifungal agent with activity against a large number of medically important fungal pathogens, including Aspergillus spp., Candida spp., Cryptococcus neoformans, Zygomycetes, and Fusarium spp. (Cuenca-Estrella et al., 2006) Commercially available posaconazole includes oral suspension, tablets, and an intravenous formulation (Duarte et al., 2014, Krishna et al., 2012, Maertens et al., 2014). It is indicated for the prophylaxis of high-risk neutropenic (acute myeloid leukemia and myelodysplastic syndrome) patients and in severe graft-versus-host disease (Ullmann et al., 2007, Walsh et al., 2007), as well as for the treatment of oropharyngeal candidiasis. The European Medicines Agency has also approved the use of posaconazole as salvage therapy in refractory aspergillosis and infections due to Zygomycetes (Greenberg et al., 2006, van Burik et al., 2006). The recommended therapeutic dose of an established infection is 800 mg/day, divided equally and administered 3–4 times per day for appropriate drug exposure. Two randomized clinical trials have shown posaconazole to be more efficient than other systemic antifungals, both reporting a significant reduction in breakthrough invasive fungal infection (Cornely et al., 2007, Groll and Walsh, 2005, Ullmann et al., 2007).

The pharmacokinetic (PK) profile of posaconazole is characterized by a strong influence of food on the absorption process and a minor metabolism by cytochrome P450 isoforms; furthermore, it has a long elimination half-life and a large apparent volume of distribution postoral administration, suggesting prolonged and extensive tissue distribution. This profile has been broadly studied in animal models in phase I, rising single-dose and multiple-dose studies with healthy subjects with a wide range of doses (Courtney et al., 2003, Nomeir et al., 2000). In addition, dose-related plasma concentration increases have been demonstrated (Courtney et al., 2004, Krishna et al., 2009a, Krishna et al., 2009b, Li et al., 2010).

Further knowledge on tissue drug penetration could help in the evaluation and design of specific dosing regimens against potential fungal pathogens. The importance of tissue concentration for antibacterial agents has been extensively reviewed, although poor attention has been paid to the currently available antifungal agents. Most data related to tissue distribution of antimycotics have been described in animal models of infection; human data from case studies through autopsies and small clinical studies have also been carried out (Felton et al., 2014). It is worth mentioning that lipophilic drugs have been reported to concentrate to high levels within cells, contributing to alter the initiation of infection. Moreover, a recently published study reports significant posaconazole accumulation in human biopsy specimens (Blennow et al., 2014).

In general, preclinical infection models have been successfully used to evaluate antifungal PK and pharmacodynamic (PD) properties. Experimental PK/PD studies in humans have increasingly demonstrated to be predictive of therapeutic outcomes (Siopi et al., 2014). Further insight on the distribution of the antifungal agent in the body could help understand the mechanism involved fungal infection progression (Autmizguine et al., 2014).

In this study, we aim to evaluate the PK behavior of posaconazole in serum and tissue samples using a rat model of aspergillosis and estimate its usefulness in establishing exposure–response relationships. It provides a valid tool to be extrapolated to humans.