MycologyBlood and tissue distribution of posaconazole in a rat model of invasive pulmonary aspergillosis
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.
Section snippets
Animals and infection
The present study was carried out in a rat model of invasive pulmonary aspergillosis, as described elsewhere (Gavaldà et al., 2005). All experiments on the animals were approved by the ethics committee of Animal Research of the Vall d'Hebron Hospital (ref. number PI081206). Female SPF Wistar rats weighing between 180 and 200 g (Harland Iberica, Barcelona, Spain) were housed in cages with high-efficiency particulate arrestance filters and fed with a protein 8% w/w diet and sterile water ad
Chromatography
A partial method validation was performed. Linearity was assessed by linear regression (best fit obtained when plotting peak areas measured by HPLC against posaconazole concentration).
For both matrices (serum and lung tissue), the standard curve was linear over a concentration range of 0.125–16.0 μg/mL, with a correlation coefficient of 0.99. The lower limit of quantification and the limit of detection were 0.125 μg/mL and 0.06 μg/mL, respectively. In addition, the upper limit of quantification
Discussion
In this study, we analyzed the distribution of posaconazole in an immunosuppressed rat model of invasive pulmonary aspergillosis receiving oral posaconazole therapy. Our results show that posaconazole exposure (expressed as posaconazole concentration in blood) is linear with respect to the daily dosage, including with the highest tested dose (64 mg/kg/day); this allowed estimating the AUC by linear extrapolation. Other studies using similar models report comparable results regarding posaconazole
Funding
This study has been financed by a research project from the Fondo de Investigaciones Sanitarias, FIS_ISCIII (Ref. PI09/0624). E. Cendejas-Bueno was a predoctoral grant holder from the Instituto de Salud Carlos III (grant AFTDOC 11/02, Spain), Currently, E. CendejasBueno has a Juan Rodés contract from the Instituto de Salud Carlos III (JR 14/00027), developed at the La Paz University Hospital. A. Forastiero received a fellowship from the Agencia Española de Cooperación Internacional para el
Transparency declarations
All authors declare no conflicts of interest.
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