Human tissue distribution of posaconazole after allogeneic stem cell transplantation

Ref ID: 19359

Author:

O. Blennow, J. Mattsson, E. Eliasson, T. Pettersson and
M. Hassan

Author address:

Karolinska University Hospital, Stockholm, Sweden; Centre for
Allogeneic Stem Cell Transplantation, Karolinska University
Hospital, Stockholm, Sweden; Department of Clinical
Pharmacology, Karolinska University Hospital, Stockholm,
Sweden and Expe

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objectives A growing body of evidence has suggested that therapeu-
tic drug monitoring is required for posaconazole but as of today no
data exist regarding the relationship between the concentration in
plasma and the concentration in human tissues of interest in fungal
infections. The objective of this study was to analyze posaconazole
tissue concentration in patients receiving posaconazole prophylaxis
because of GVHD and compare those to the concentration in plasma
in blood samples.
Methods Tissue samples were obtained during routine autopsy from
seven patients that had undergone allogeneic HSCT and received or
had received posaconazole as fungal prophylaxis either at the time of
death or just prior to the time of death. Biopsies were homogenized
and the concentration of posaconazole was analyzed using the rou-
tine LC-MS based method. The standard curves used were derived
from spiked homogenized rat tissues. One to three blood samples per
patient were collected during the treatment period with posaconazole
and concentration of posaconazole was analyzed using the routine
LC-MS based method.
Results Posaconazole dosages, plasma concentrations, the time from
last administered posaconazole dose to death, the time from biopsy to
analyze, and tissue concentrations are presented in Table 1. The rela-
tionship between the tissue concentrations of posaconazole in differ-
ent organs is shown in Figure 1. Setting the concentration of
posaconazole in liver tissue as 100%, the concentration of posaconaz-
ole in brain tissue varied between 4% and 12% in six evaluable
patients. Excluding one outlier for each organ, the corresponding
numbers for heart tissue were 27-76%, for lung tissue 23-62%, and
for kidney tissue 48-78%.
Only one patient received the recommended prophylaxis dose
of 200 mg q8 h. Plasma concentrations for this patient were
700 ng/ml after five days of treatment and 390 ng/ml at the day of
death, giving a mean concentration of 550 ng/ml. The posaconazole
concentration found in brain tissue in this patient was approximately
60% of the mean concentration found in plasma. In all other tissues
examined, the concentrations exceeded the one found in plasma,
ranging from 160% for lung tissue to 470% for liver tissue.Conclusions Accumulation of posaconazole compared to plasma lev-
els were seen in liver, kidney, lung and heart tissues, with values
well over MIC for most clinically important Candida and Aspergillus
species, even when plasma concentrations were just under the pro-
posed prophylaxis threshold of 700 ng/ml. These results, together
with the introduction of posaconazole in a solid tablet formulation
that administered once daily resulted in Cavg of 1300 ng/ml, indi-
cates that plasma concentration determinations as part of routine
monitoring of patient on posaconazole prophylaxis may become
superfluous, and perhaps should be restricted to more specific indica-
tions such as therapeutic failure. Posaconazole concentration in
brain tissue was low, approximately half of the plasma levels. Pend-
ing corroborative studies it seems reasonable to have a significantly
higher target plasma concentration when treating fungal infections
in CNS compared to other infectious loci, and based on the present
results around 2000 ng/ml might be more appropriate.

Abstract Number: o2.2

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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