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18
D.A. Marsh
https://t.me/med1917
10-year outlook and may include marketing experts, drug delivery scientists, a licensing
expert, and a patent lawyer. Members of the team ask and answer questions for senior
management such as: What is currently available to treat the targeted disease? What
is the total market for this lesion? How long will it take to bring the proposed drug
delivery system to market? Will the product be protected by patents and will it have
freedom to practice? Are there superior drug delivery systems, which should be
licensed from an outside individual or group? What will the competition look like by
the time the product is introduced? Will the proposed product be sufficient to take a
reasonable piece of the competitions market at the time of approval?
It should be understood that by the time the new drug is approved, perhaps
some 5–10 years hence, the current-year competition may have a strong foothold
in the world market; consequently, it may take a significant advantage for the newcomer to compete. Furthermore, one must assume that the competition is not
standing still; it is developing its next generation pharmaceutical. Therefore, there
is a clear need to design a product, which will not only be superior to the competitor’s
current product but will leapfrog the competitor’s next generation therapy.
Depending on the team’s findings and senior management’s direction, the strategic team may provide invaluable input into the current and future drug delivery
system requirements. For example, the team may nix a concept for a product
designed to be equivalent to the current Lucentis intravitreal injection because, by
the time this new product reaches market, it is likely that it will be competing with
the next generation of that drug. The team might redirect the research efforts toward
leapfrogging the competition 7 years down the road.
This strategic logic applies to nonprofit organizations. Being free of the obligation
to run a profitable business, nonprofits have more latitude to synthesize and investigate
new drugs, discover novel disease-mitigating pathways, develop new drug delivery
devices, and/or evaluate “out of the box” therapies. Why, then, would such organizations waste precious resources trying to match a therapy, which is currently available?
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Chapter 2
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Microdialysis for Vitreal Pharmacokinetics
Ravi D. Vaishya, Hari Krishna Ananthula, and Ashim K. Mitra
Abstract Microdialysis has been an instrumental sampling technique to study ocular
pharmacokinetics without sacrificing a huge number of animals. It has undergone
significant transformations in the last decade and several animal models have been
established for sampling inaccessible posterior segment tissues such as vitreous
humor. Remarkable progress has been made in the probe design and validation techniques. In the following chapter we have discussed the principle and development
of various animal models related to posterior segments.
Abbreviations
ACV Acyclovir
AZdU 3¢-Azido-2¢,3¢-dideoxyuridine
AZT Zidovudine
E17bG 17-b-glucoronide
GCV Ganciclovir
PLGA Poly(dl-lactide-co-glycolide)
PLGA-PEG-PLGA Poly(dl-lactide-co-glycolide)-poly(ethylene glycol)-
poly(dl-lactide-co-glycolide)
VACV Val-acyclovir
VVACV Val-val-acyclovir
A.K. Mitra (*)
Division of Pharmaceutical Sciences, University of Missouri-Kansas City, School of Pharmacy,
2464 Charlotte Street (HSB-5258), Kansas City, MO 64108-2718, USA
e-mail: mitraa@umkc.edu
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_2,
© American Association of Pharmaceutical Scientists, 2011
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2.1 Introduction
Several retinal diseases such as diabetic macular edema, retinoblastoma and age-related
macular degeneration require chronic treatments. Usually therapeutics is delivered
by intravenous, subconjunctival, intravitreal (IVT) or peribulbar routes. Precise
knowledge of various pharmacokinetic parameters is necessary for designing a
dosage regimen. Drug release from sustained release formulations must be modulated so that drug level can be precisely maintained within the therapeutic window
at the target site. The target site is usually retina, Bruch’s membrane and choroid
for most posterior segment diseases. However, it is impossible to measure drug
concentrations at these sites unless the animal is sacrificed and tissues are assayed
for drug concentrations. However, in order to construct a pharmacokinetic profile
by this method, 6–20 animals for each time interval with at least ten time points are
necessary to adequately define the absorption, distribution and elimination processes. Overall, 120–150 animals are required for single dose pharmacokinetic
study. In this scenario, microdialysis offers an important sampling technique that
can be an alternative method to avoid the use of huge number of animals. It can also
allow continuous sampling. Previously, microdialysis has been extensively applied
to measure concentrations of drugs or endogenous substances such as neurotransmitters in the brain and eye. So far this method has been employed for sampling
body fluids including blood, vitreous humor, aqueous humor and extracellular
fluids. Since late 1980s, the technique has undergone several major modifications
for sampling analytes in vitreous as well as aqueous humor.
Microdialysis was utilized by Kalant et
tration in the blood. In mid 1970s, neuroscientists modified the technique for
measuring concentration of dopamine in rat brain (Ungerstedt and Pycock 1974).
In 1987, Gunnarson et al. for the first time employed microdialysis to measure free
amino acids in the vitreous humor of albino rabbits (Gunnarson et al. 1987). Since
then, various investigators have employed microdialysis to understand pharmacokinetics of drugs as well as endogenous substances in vitreous fluid. So far, rabbits,
rats, cats and pigeons have been utilized for vitreal microdialysis, although rabbits
represent the most widely employed animal model. In the following sections, the
advancements in the technique and its applications in posterior segment pharmacokinetics have been discussed.
al. (1958) to measure steroid concen-
2.2 Posterior Segment as a Sampling Site
Vitreous chamber is the sampling site for posterior segment microdialysis. It represents a connective tissue consisting of ~99% water with dissolved chondroitin
sulfate, collagen, mucopolysaccharides such as glycosaminoglycans and hyaluronates providing gelatinous consistency (Rittenhouse and Pollack 2000). In adults no
vitreous humor is regenerated (Rittenhouse and Pollack 2000). In the posterior
segment, the photoreactive tissue i.e., retina is nourished by choroidal and retinal
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2 Microdialysis for Vitreal Pharmacokinetics
EPITHELIAL BARRIER TISSUE BOUNDARY SOLID PHASE BLOOD VESSEL
CIRCULATING FLUID
FLUID FLOW
MUSCLE TARGET SITE
ACTIVE TRANSPORT
strong continuous
lowhigh
fenestrated
complete
tight
weak porous
d
a
c
h
i
l
v
z
s
Diffusion resistance
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Fig. 2.1 Diagrammatic representation of the routes of elimination of drugs from the vitreous of
the eye
blood vessels. Movement of nutrient and waste molecules from the blood to retina
is controlled by specific transport systems (Fig.
molecules such as amino acids and neurotransmitters to and within vitreous
2.1). However, movement of these
humor is via simple diffusion (Fig. 2.1) (Gunnarson et al. 1987). With respect to
mass transfer, vitreous humor can be viewed as unstirred static fluid (Hughes et al.
1996). The globe is a closed system and does not allow sampling of tissues without
irreversible damage. In such case, microdialysis plays an important role as a sampling
technique which significantly reduces the number of animals required for pharmacokinetic studies.
2.3 Principle of Microdialysis
Microdialysis works on the principle of dialysis wherein a microdialysis probe is
inserted in the tissue or fluid of interest. The probe has a semipermeable dialysis membrane which is circulated with physiological solution at a constant flow rate (Fig. 2.2).
24
R.D. Vaishya et al.
out
in vitro
in
Recovery .
C
C
=
Cos in ECF
Blood Capillary
Dialysate
Ces
Cec
Perfusate
Cic
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Fig. 2.2 Microdialysis schematics. Microenvironment within and surrounding the microdialysis
probe in vivo. The solid and dashed line segments schematically represent the non-permeable
probe wall and semipermeable membrane, respectively. Open and filled circles represent molecules of solute of interest and retrodialysis calibrator, respectively. Squares and triangles represent
macromolecules which may bind solute and or calibrator but which are not recovered by dialysis.
Arrows indicate the direction of transport
Following insertion of microdialysis probe, the concentration gradient across the
semipermeable membrane causes the solute to diffuse in or out of dialysis probe.
In order to avoid change in composition (ionic strength) of the surrounding fluid,
the composition of perfusate should be similar to the fluid surrounding the dialysis
membrane. Movement of solute molecules is also dependent on the molecular
weight cut off (MWCO) of dialysis membrane. The process, governed by concentration gradient, never reaches the equilibrium since the perfusate is constantly
circulated through the probe. Therefore, concentration in the dialysate is not
same as that of vitreous. Analyte concentration in the dialyzing fluid (vitreous
humor) can be determined from recovery, also known as extraction efficiency or
relative recovery.
2.3.1 Extraction Efficiency/Recovery
Recovery is a ratio between the concentration of analyte in dialysate (C
surrounding the probe (Cin). The concentration of analyte in dialysate is a fraction
of that present in the fluid surrounding the probe. Therefore, in vitro probe recovery
is a key parameter for analyzing in vivo microdialysis data. In vitro probe recovery
may be calculated by (2.1).
) and fluid
out
(2.1)
25
2 Microdialysis for Vitreal Pharmacokinetics
out
ˆ
C
in
ˆ
C
out
in
in vitro
ˆ
ˆ
.
Recovery
C
C =
in out
internal standard
in
Recovery ,
CC
C
-
=
internal standard
analyte
Recovery
Recoveryratio ,
Recovery
=
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Following determination of recovery with defined parameters such as flow rate,
(2.2) can be utilized to transform dialysate concentration (
concentration (
).
) into actual vitreous
(2.2)
Absolute recovery is the amount of analyte over a definite period of time. It is the
product of relative recovery (R), flow rate (F) and concentration of the analyte (C)
(Wages et
al. 1986).
Relative recovery can also be calculated by retrodialysis. In this method, an
internal standard is perfused through dialysis tube and the loss in internal standard
is measured along with the analyte from the dialysate. Recovery of both analyte
and internal standard are calculated. Recovery, fractional loss of internal standard
during dialysis, is calculated with (2.3).
Cin is the concentration of internal standard entering probe; C
(2.3)
is the concentration
out
of internal standard exiting the probe. Recovery of the internal standard and analyte
can be compared taking ratio, given in (2.4).
(2.4)
A number of factors may influence in vitro probe recovery including perfusate
flow rate and composition, temperature, properties of the membrane, probe design,
analyte concentration and molecular weight. For example, the relative recovery
decreases as the perfusate flow rate is raised (Wages et
al. 1986). Among these,
temperature and flow rate of perfusate are most critical factors influencing in vitro
recovery. Wang et al. studied the relationship between perfusate flow rate and
in vitro recovery utilizing zidovudine (AZT) as analyte and 3¢-azido-2¢,3¢dideoxyuridine (AZdU) as internal standard. Recovery decreased exponentially
with the increase in flow rate (Wang et al. 1993) (Fig. 2.3). Therefore, the rate of
perfusate in dialysis probe is a key parameter that needs to be considered while
optimizing microdialysis parameters. Usually a flow rate of 2 mL/min is preferred
for most experiments. Figure 2.4 explains the influence of temperature on recovery
at different perfusate flow rates (Wages et al. 1986). Recovery of DOPAC was studied
by retrodialysis and effect of temperature on recovery was examined. Recovery was
highest at 37°C and least at 23°C. This difference may be attributed to elevation in
diffusion coefficient with rising temperature (Wages et al. 1986).
It has been well documented that in vivo recovery is always less than in vitro
recovery during brain microdialysis studies (Amberg and Lindefors 1989). This may
lead to misinterpretation of drug concentration data. During brain microdialysis, the
26
R.D. Vaishya et al.
100
90
RECOVERY (%)
80
70
37°C
23°C
60
50
.04.08 .12
FLOW RATE (
µL/MIN)
.16 .20 .24
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Fig. 2.3 Effect of flow rate on in vitro recovery of zidovudine (AZT) and loss of 3¢-azido-2¢,3¢dideoxyuridine (AZdU) during microdialysis and retrodialysis. Filled square and circle represents
loss of AZT and AZdU. Empty square and circle represents recovery of AZT and AZdU
Fig. 2.4 Effect of temperature on in vitro recovery of DOPAC at different flow rates by retrodialysis
analyte concentration is measured in the extracellular fluid. Substrate diffuses from
interstitial space in a tortuous path. Moreover, the analyte may partition inside the
cells and therefore its concentration in the dialysate may not reflect the actual
concentration when tissues are sampled with microdialysis. Movement through
tortuous path and partitioning into cells may lower in vivo recovery of substrate.
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2 Microdialysis for Vitreal Pharmacokinetics
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However, this is not the case with vitreous humor since it is uniform and has
insignificant radial or spherical dependence on diffusion coefficient of substrates
(Maurice 1957). This is because vitreous humor is >99% water and solid content
(collagen fibrils) is about 0.2%. At such a low concentration, distance between two
collagen fibrils is 2 mm, which would not hinder the diffusion of molecules in vitreous
(Maurice 1959). Therefore, the rate of diffusion of a molecule in vitreous humor
remains the same as in free solution despite the viscous nature of vitreous fluid.
2.4 Posterior Segment Microdialysis: Development
of Models and Applications
Invasive nature of microdialysis procedure has restricted its application to animals.
Various species have been employed to develop and validate microdialysis model,
including rats (Katayama et al. 2006; Hosoya et al. 2009), rabbits, cats (Ben-Nun
et al. 1988), zebrafish (Puppala et al. 2004) and pigeon (Adachi et al. 1995, 1998).
Rabbits have been the animal model of choice for vitreal pharmacokinetics and it
had been widely used for in vivo studies involving amino acid and neurotransmitter
release (Gunnarson et al. 1987). More importantly, rabbits have fairly large posterior
segment with adequate vitreous humor volume (1–1.5 mL) to allow probe implantation. However, it differs from human eyes in several aspects such as absence of
macula, lower corneal thickness, slower blinking reflux, avascular retina and the
absence of uveoscleral outflow pathway (Rittenhouse and Pollack 2000). All these
differences must be taken into account while reporting the pharmacokinetic data.
Rabbit models developed so far can be divided into two main categories (a) anesthetized animal model, (b) conscious animal model.
2.4.1 Anesthetized Animal Models
Microdialysis has been a well-established technique to study neurotransmitter release
in brain. In late 1980s, several investigators employed microdialysis to understand
neuro-biochemistry and visual function by measuring released endogenous factors.
Also the effects of various experimental conditions such as ischemia and laser
photocoagulation were investigated by pharmacokinetics of specific markers.
Gunnarson et al. (1987) sampled preretinal vitreous humor to identify and quantify
amino acids. The design of probes was derived from the probes used in brain microdialysis, where dialysis probe was mounted on stainless-steel cannula. Louzada-Junir
et al. (1992) studied the effects of ischemia on the release of excitatory amino
acids (EAAs), like glutamate, into vitreous. These investigators observed a strong
correlation between release of glutamate during reperfusion and cell death. In another
study, Stempels et al. (1994) performed vitreal microdialysis to determine the
concentration of released catecholamines, following laser photocoagulation of
the retina at a particular wavelength.
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