Download Lower Pediatric Oral Bioavailability of Voriconazole is Not Due to

Lower Pediatric Oral Bioavailability of Voriconazole is Not Due to Lower Intestinal Bile Salt
Concentration in Children
Arti R.
1 Division
1
Thakkar
and Dhiren R.
1
Thakker
of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Purpose
Methods
Voriconazole is a second-generation triazole antifungal
Ex Vivo Permeation Studies of Voriconazole:
agent with potent activity against a broad spectrum of
Absorptive transport of voriconazole was measured across mouse intestinal tissue in
clinically
including
an Ussing-type diffusion chamber. The apical side of tissue segments was exposed
Aspergillus, Candida, Cryptococcus neoformans, and
for 3 hours to voriconazole (1mM) dissolved in Krebs-Bicarbonate Ringer buffer
certain less common molds. It is used for treating life-
(control) or Fasted-State Simulated Intestinal Fluid (FaSSIF) containing 1mM
threatening fungal infections in children, especially in
(pediatric) or 3mM (adult) bile salts. Basolateral (receiver) and apical (donor)
immunocompromised patients, and is marketed as Vfend
solutions and tissue lysates were analyzed for voriconazole and its N-oxide
(Pfizer, New York, NY). Voriconazole has an absolute
metabolite with high-performance liquid chromatography / UV detection (HPLC-UV),
bioavailability (BA) of ~96% in adults, whereas in
using diclofenac sodium as an internal standard.
children of 2-11 years of age, its BA is only ~45-65%.
Voriconazole and Voriconazole N-oxide Analysis:
Also,
HPLC-UV detection was employed to quantify voriconazole and its major metabolite,
significant
children
fungal
exhibit
pathogens,
~3-fold
higher
voriconazole
clearance compared to adults1.
voriconazole N-oxide. An agilent 1100 HPLC system (Agilent Technologies, Santa
Voriconazole is cleared predominantly via oxidative
Clara, CA) and a Nova-Pak C18 column (150 × 3.9 mm, 4 μm) were used to separate
metabolism by cytochrome P450 (CYP) 3A4, CYP2C19,
the samples. Analytes were eluted from the column with a linear gradient of mobile
flavin-containing monooxygenases (FMO) and, to a
phase A/B (v/v) starting at 90:10 at 0 minutes to 15:85 at 10 minutes at a 0.8 mL/min
lesser extent, CYP2C9. The two major metabolites of
flow rate. Mobile phase A consisted of 5 mM ammonium acetate with 0.1% formic
voriconazole
acid and mobile phase B consisted of acetonitrile with 0.1% formic acid. The
are
N-oxide
and
hydroxymethyl
retention time was 5.5 minutes for voriconazole, 6.2 minutes for diclofenac sodium
voriconazole (Fig 1)2.
Figure 1. Voriconazole and its metabolites
and 4.8 minutes for the voriconazole N-oxide. Peak areas were measured at 265 nm
for diclofenac sodium and voriconazole N-oxide, and at 254 nm for voriconazole.
Results
Voriconazole
Voriconazole N-oxide
Hydroxymethyl Voriconazole
Figure 3: Absorptive Transport of Voriconazole across Mouse Intestinal Tissue
Various factors3,4 such as age-related changes in
gastrointestinal (GI) physiology (transit time, pH, GI fluid
composition, specifically bile salt concentrations) and
intestinal/hepatic drug metabolizing enzymes, as well as
formulation parameters (dose volume, solubility) can
contribute to differential absorption of voriconazole in
children versus adults (Fig 2).
This study aims to evaluate the effect of lower intestinal
bile salt concentrations in children (compared to adults)
Voriconazole absorptive permeability was significantly
higher in FaSSIF media containing 1 mM (Papp = 59.01
nm/sec, p<0.05) or 3 mM (Papp = 60.49 nm/sec, p<0.01) bile
salts compared to that observed with control KBR media
(Papp = 22.51nm/sec). No difference in voriconazole
absorptive permeability was observed between 1 mM and 3
mM bile salt concentrations. Voriconazole N-oxide was
detected in mouse intestinal tissue and in the apical, but
not the basolateral compartment, and was not present in
sufficient quantities to affect voriconazole Papp estimates.
Conclusions
 As anticipated, bile salts increase the transport rate of
voriconazole across mouse intestinal epithelium,
presumably by increasing its solubility.
 However, our observation that reducing bile salt
concentration from 3 mM (adult intestinal concentration)
to 1 mM (pediatric intestinal concentration) does not
affect voriconazole permeability suggests that the lower
oral bioavailability of voriconazole in children compared
to adults is not due to differences in intestinal fluid
composition.
 Our results support the predictions of the PBPK model
developed in our laboratory5 that intestinal first-pass
metabolism likely contributes to lower oral bioavailability
of voriconazole in children compared to adults.
References
on oral absorption of voriconazole.
Figure 2. Factors Responsible for Low BA in Children
- GI volume
- GI fluid composition
- Expression and
ontogeny of enzymes
- Formulation-related
properties
Figure 4: Voriconazole Papp in Mouse Intestinal Tissue
L
O
W
Voriconazole absorptive transport rate was 3-fold greater in FaSSIF media
containing 1mM or 3mM bile salts compared to that observed with control KBR
B
A
media. Voriconazole is BCS class II drug with low solubility due to lipophilic nature.
Bile salts solubilize the drug which leads to increased rate of transport in FaSSIF
media. Concentration (1mm and 3mm) of bile salts had no effect on voriconazole
absorptive transport.
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