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Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma
Gisela Velez, MD, MPH;
Peng Yuan, PhD;
Cynthia Sung, PhD;
Ginger Tansey, DVM;
George F. Reed, PhD;
Chi-Chao Chan, MD;
Robert B. Nussenblatt, MD;
Michael R. Robinson, MD
Arch Ophthalmol. 2001;119:1518-1524.
ABSTRACT
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Objective To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic
agents in the rabbit eye for the potential treatment of primary intraocular
lymphoma and other intraocular malignancies.
Methods The ocular pharmacokinetics of intravitreal methotrexate sodium (400
µg) was studied in 10 New Zealand white rabbits, and a single-compartment,
first-order elimination model was used to calculate the drug half-life. With
the use of these data, a treatment schedule using serial injections of intravitreal
methotrexate and single injections of fluorouracil and dexamethasone sodium
phosphate was developed. This schedule was studied in 4 New Zealand white
rabbits to explore the combined toxicity of these agents.
Results Methotrexate vitreous levels, following a 400-µg intravitreal
injection, remained therapeutic (>0.5µM) in the rabbit eye for 48 to
72 hours. Intravitreal methotrexate, combined with fluorouracil and dexamethasone,
showed no evidence of drug toxicity as determined by electroretinography and
histopathologic examination.
Conclusions A treatment schedule for primary intraocular lymphoma consisting of
methotrexate intravitreal injections every 48 to 72 hours provides therapeutic
drug concentrations in the vitreous and, in combination with fluorouracil
and dexamethasone, appears to be safe in the rabbit eye.
Clinical Relevance Although responsive to conventional chemotherapy or radiotherapy, recurrence
of ocular involvement with primary central nervous system lymphoma occurs
in more than 50% of treated cases. Anecdotal reports of the use of intravitreal
chemotherapy for primary intraocular lymphoma have been encouraging. However,
animal data on the pharmacokinetics and toxicity of combined intravitreal
agents for the treatment of this disease are lacking.
INTRODUCTION
LOCAL OCULAR therapy results in high ocular drug concentrations and
has been successful in animal models of ocular malignancy.1-5
In a limited number of reports on potential treatment measures for primary
intraocular lymphoma (PIOL), intraocular injections of methotrexate6 or methotrexate and thiotepa7
have been used. Unfortunately, the data on the long-term safety and efficacy
of locally injected antineoplastic agents into the eye are lacking.
Primary intraocular lymphoma, or primary central nervous system lymphoma,
is a non-Hodgkin lymphoma that may arise from the brain, spinal cord, leptomeninges,
or eye. It is associated with a high mortality, with ocular involvement in
25% of patients.8-9 Treatment
of primary central nervous system lymphoma with chemotherapy, with or without
radiation, improves survival. However, ocular disease recurs in 50% of cases.10 Locally injected cytotoxic agents are a viable treatment
option for these patients.
The choices of antineoplastic agents available for local ocular therapy
are limited because most are toxic to the retina and optic nerve.11-12 However, some antimetabolites have
been shown to be safe. Methotrexate has been shown to be clinically nontoxic
when injected into human eyes at doses of 400 µg.6
Similarly, fluorouracil12-16
and corticosteroids,17-18 at doses
of up to 1 and 4.8 mg, respectively, have been shown to be nontoxic when injected
into animal eyes. These agents have also been used in human eyes safely.19-20 Although known to be active against
non-Hodgkin lymphoma,10, 21-26
the pharmacologic characteristics and toxic effects of local ocular injections
using these agents together have not been well examined.
The pharmacologic characteristics of local injections of methotrexate
in the cerebral spinal fluid has been well studied and used extensively for
central nervous system disease.27 Protracted
exposure times of methotrexate (3 days to 4 weeks) by using frequent low-dose
injections or continuous infusions have been shown to improve tumor cell kill
and to reduce local and systemic toxic effects.28-30
Intrathecal therapy using multifractionated dosing of methotrexate is now
standard of care in the treatment of leptomeningeal cancers. Combining methotrexate
with other agents, such as other antimetabolites and corticosteroids (so-called
triple therapy), has been used intrathecally to enhance tumor response rates
in patients with meningeal leukemia.31 Extrapolating
from the experience of using combination chemotherapy injected directly into
the cerebral spinal fluid, triple intravitreal therapy using methotrexate,
fluorouracil, and dexamethasone sodium phosphate, may lead to more durable
treatment responses in patients with intraocular malignancies such as PIOL.
The cytotoxic effects of methotrexate are enhanced when fluorouracil
is given 24 hours after methotrexate exposure, and this antineoplastic synergism
may improve treatment responses with intravitreal chemotherapy.32-34
Methotrexate and fluorouracil are highly cell-cycle dependent, acting primarily
during the S phase (DNA synthesis) of the cell cycle.35
In contrast, corticosteroids are cell-cycle nonspecific and are cytotoxic
to lymphoma cells at all stages of the cell cycle.36-39
Therefore, for tumor cells not treated by methotrexate and fluorouracil (ie,
cells in resting phase or G0), a single intravitreal injection
of dexamethasone was given in our study following the last methotrexate injection.
The intravitreal dose of dexamethasone sodium phosphate used was 500 µg,
since higher doses, or multiple dosing, are associated with ocular toxic effects.18, 20
The purpose of this study was to investigate the pharmacokinetics of
intravitreal methotrexate in the rabbit eye to optimize the dosing interval.
Furthermore, this study examined the safety of a treatment schedule using
serial injections of intravitreal methotrexate and single injections of fluorouracil
and dexamethasone in the rabbit eye.
MATERIALS AND METHODS
PART 1: PHARMACOKINETICS OF INTRAVITREAL METHOTREXATE
The in vitro activity of methotrexate for 63 different cell lines has
been investigated at the Developmental Therapeutics Program, National Cancer
Institute, Frederick, Md, and results indicate that the therapeutic levels
of methotrexate range from 0.1 to 1.0µM with a mean 50% growth inhibition
of 0.32µM.40 Based on the treatment of
one patient with PIOL, a single intravitreal injection of 400 µg of
methotrexate yielded cytotoxic levels in the vitreous for approximately 72
hours.7 We investigated the pharmacokinetics
of intravitreal methotrexate sodium in the rabbit eye. We then used these
data to design a treatment schedule combining intravitreal methotrexate with
intravitreal fluorouracil and dexamethasone.
Ten New Zealand white rabbits (20 eyes) of either sex weighing 2 to
3 kg (Covance Laboratories Inc, Vienna, Va) were used, and the procedures
adhered to the guidelines from the Association for Research in Vision and
Ophthalmology for animal use in research. Food and water were supplied to
the rabbits ad libitum. Animals were anesthetized with 35 mg/kg of intramuscular
ketamine hydrochloride (Fort Dodge Inc, Fort Dodge, Ind) and 5 mg/kg of intramuscular
xylazine hydrochloride (Phoenix Scientific Inc, St Joseph, Mo), and 1% proparacaine
hydrochloride ophthalmic drops (Allergan America, Hormigueros, Puerto Rico)
were used topically on the eye. After adequate anesthesia and akinesia were
obtained, a lid speculum was placed and each eye was injected 3 mm behind
the surgical limbus in the superotemporal quadrant separately with 32 µL
of a 1:1 dilution in balanced salt solution (BSS) (Alcon Laboratories Inc,
Fort Worth, Tx) of methotrexate sodium (preservative free, 25 mg/mL in 2-mL
vials; distributed by Immunex, manufactured by Lederle Parenterals Inc). The
total dose for each injection was 400 µg of methotrexate sodium. One
rabbit was used as a control and injected in both eyes with 32 µL of
BSS. Two rabbits receiving methotrexate injections in both eyes were euthanized
with a pentobarbital overdose (Beuthanasia-D Special; Schering-Plough Animal
Health Corp, Kenilworth, NJ) at each of the following intervals after injection:
1.5, 5.5, 7.5, 23.5, and 47.5 hours. The eyes were enucleated and immediately
frozen at –70°C for later dissection and drug extraction. The time
from enucleation to freezing was rapid (<10 seconds), which limited postmortem
drug redistribution. The control rabbit was euthanized and both eyes were
enucleated 24 hours after injection.
The eyes were dissected while frozen by first removing the cornea and
lens from the globe. The vitreous was then expressed and isolated for drug
extraction. The methotrexate was extracted from the tissues by the addition
of an equivalent weight of high-performance liquid chromatography (HPLC) grade
acetonitrile (Burdick & Jackson Inc, Muskegon, Mich), sonicated for 3
minutes at a level of 3.5 with an ltrasonic processor (GEX 600; Thomas Scientific,
Swedesboro, NJ), and incubated for 24 hours at room temperature. The samples
were spun down in a centrifuge (TOMY MTX-150; Peninsula Laboratories Inc,
Belmont, Calif) for 15 minutes at 10 000 rpm, and the supernatants were
submitted for HPLC analysis.
Samples were analyzed by using a computerized HPLC system (HP1100; Hewlett
Packard, Agilent Technologies, Palo Alto, Calif) equipped with a UV detector,
an autosampler, a gradient pump, and a workstation (HP Kayak; Hewlett Packard)
that controls the operation of HPLC and analyzes the data. A chromatography
column (5 µm, 250 x 4.6 mm) (Ultrasphere C-18; Beckman Coulter,
Inc, Fullerton, Calif) was used for separation and detection was set at 302
nm. The flow rate used was 1.0 mL/min, with a mobile phase of 85% of 63mM
sodium phosphate dibasic and 19mM citric acid and 15% acetonitrile. A five-point
standard curve of methotrexate (0.5-150 µg/mL) was constructed with
correlation coefficient 1.000, and methotrexate concentrations of samples
were calculated on the basis of peak areas.41
Methotrexate concentration was determined for each vitreous specimen
(20 eyes total for all time points, 4 eyes per time point or 2 eyes for each
of 2 rabbits per time point). All data were then fit to a single-compartment,
first-order elimination model as shown in equation 1 with 1/C2pred weighting (where Cpred is the concentration predicted by the best fit of the data to a
single exponential decay; and the weighting scheme assumes that the error
in the concentration value is proportional to the concentration) to obtain
estimates of the volume of distribution (Vd)
and elimination rate constant (k):
where C indicates concentration, t is time after administration of the drug, exp(-k · t)
is equivalent to e(-k · t) (e to the
power of [-k · t]) in which e is Euler's number with a numerical value equal to 2.71828.
The clearance was calculated as the product of Vd
and k, and the half-life was calculated as 0.693/k.
Since at each time point methotrexate concentrations in both eyes of
2 rabbits were measured, the usual calculation of SD, which is based on the
statistical independence of each measurement, cannot be applied. Therefore,
the SD for each time point was derived from the variance components model,
which recognizes that the variance of these data was the sum of 2 components:
that between rabbits and that within rabbits.
PART 2: OCULAR TOXIC EFFECTS OF COMBINATION INTRAVITREAL CHEMOTHERAPY
Data from part 1 of the study indicated that an intravitreal injection
of methotrexate sodium (400 µg) can yield therapeutic levels for 48
to 72 hours (see "Results" section). Using this information, a treatment schedule
of serial injections of intravitreal methotrexate and a single injection of
fluorouracil and dexamethasone (Table 1) was developed. The intravitreal doses of fluorouracil and dexamethasone
suggested in the table were recommended based on the reported ocular toxic
effects data in the literature.14, 16-18
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Table 1. One Cycle of Intravitreal Chemotherapy*
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Part 2 of this study examines the safety of using serial injections
of intravitreal methotrexate and single injections of fluorouracil and dexamethasone
in the rabbit eye. Doses used in this ocular toxicity test were increased
by 100% to explore the effects of maximum therapy. A total of 3 cycles, given
1 month apart, were administered to study the long-term ocular toxic effects
of combination intravitreal chemotherapy.
Four New Zealand white rabbits of either sex weighing 2 to 3 kg (Covance
Laboratories Inc) were used for this part of the study, and anesthesia was
given before injections as described herein. Drug injections were given in
the right eye of each rabbit, whereas control injections with BSS (Alcon Laboratories
Inc) of equal volume were administered in the left eye. Methotrexate sodium
(25 mg/mL, preservative free) was injected undiluted in a volume of 32 µL
for a total of 800 µg per injection. Fluorouracil (50 mg/mL, ICN Pharma
ceuticals Inc, Costa Mesa, Calif), diluted to a concentration of 25 mg/mL
with BSS, was injected in a volume of 40 µL for a total of 1000 µg
per injection. Dexamethasone sodium phosphate (Decadron, 24 mg/mL; Merck &
Co Inc, West Point, Pa) was injected undiluted in a volume of 42 µL
for a total of 1000 µg per injection. The schedule of injections was
performed as shown in Table 1.
A total of 3 cycles were administered, each cycle separated by 28 days.
Electroretinograms (ERGs) were obtained at baseline; at days 3, 5, and
9 of each treatment cycle; and at every 7 days between cycles. The ERGs were
continued for 3 months after the last cycle to examine for any latent toxic
effects. The rabbits were anesthetized using the same procedures detailed
herein, and the pupils were dilated with 1 drop of 2.5% phenylephrine hydrochloride
(Akorn Inc, Decatur, Ill) and 1% tropicamide (Alcon Inc, Humacao, Puerto Rico).
The ERGs were recorded from each eye separately after 30 minutes of dark adaptation.
A monopolar contact lens electrode (ERG-Jet, La Chaux-des-Fonds, Switzerland)
was placed on the cornea and served as a positive electrode. Subdermal needle
electrodes inserted in the forehead area and near the outer canthus served
as the ground and negative electrodes, respectively. The ERGs were elicited
by flash stimuli delivered with a photostimulator (PS22; Grass Instruments,
Quincy, Mass) at 0.33 Hz. Responses were amplified, filtered, and averaged
with a signal averager (Spirit; Nicolet Instruments Corp, Madison, Wis). Averages
of 20 responses were measured to obtain amplitude and implicit time values
of a and b waves.
Rabbits were euthanized and both eyes were enucleated 2 weeks after
the last ERG. Enucleated eyes were fixed in 10% formalin immediately after
removal. Paraffin sections through the pupillary optic nerve head axis, including
the injection sites, were stained with hematoxylin-eosin for light microscopic
examination.
To determine whether there was a difference between treated and placebo
eyes, the difference of treated minus placebo means of logarithm-transformed
ERGs at the end of the study was tested for difference from zero, adjusted
for the difference at the beginning of the study, by analysis of covariance.
The mean of treated eyes over all times minus the mean of placebo eyes was
tested by the 1-sample t test.
RESULTS
PART 1
Following a 400-µg injection, methotrexate concentration in the
vitreous declined monoexponentially, demonstrating only an elimination phase
without an observable distribution phase. The volume of distribution was 2.16
mL compared with a vitreous volume of 1.50 mL.42
Thus, methotrexate appears to distribute rapidly into a volume 1.44 times
the volume of the vitreous within the first 2 hours. The half-life of methotrexate
in the rabbit vitreous was 7.6 hours. Methotrexate levels remained above a
therapeutic level in the rabbit eye for 48 hours after an injection of 400
µg (5.25µM) (Figure 1).
The level is predicted to drop below 1µM by 66 hours. At 72 hours, the
predicted concentration is 0.58µM (0.26 µg/mL). The clearance
of methotrexate was approximately 0.20 mL/h.
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Figure 1. Methotrexate vitreous concentration
following a 400-µg injection into rabbit eyes. Symbols indicate the
mean of 4 samples; error bars, the SD of the mean. Line represents a fit of
data to a 1-compartment, first-order elimination model.
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PART 2
The ERG analysis was performed by examining the dark-adapted a- and
b-wave amplitudes of the experimental and control eyes of each rabbit at each
time point (Table 2 and Figure 2). Fluctuations in the a- and b-wave
amplitudes are noted in both the experimental (right) and control (left) eyes.
These fluctuations do not correspond specifically to the timing of injections.
A large decrease in a-wave amplitude in control and experimental eyes is noted
at 44 days after completion of the second cycle. Full recovery is noted, however,
with no statistically significant difference in the mean of the a- and b-wave
amplitudes between the treatment eyes (right) and control eyes (left) after
the final cycle (P = .11). Furthermore, there were
no significant differences in the mean ratio of the a- and b-wave amplitudes,
averaged over all the study points, between the treatment eyes (right) and
control eyes (left) (P>.20).
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Table 2. a- and b-Wave Amplitudes of the Rabbit Eyes at Each Time Point
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Figure 2. Electroretinogram showing no difference
between treatment and control eyes. A, a-Wave amplitudes in experimental (right)
and control (left) eyes during the study. B, Similar plot showing the b-wave
amplitudes during the study. Symbols indicate the mean of 4 readings; error
bars, the SD of the mean; and arrows, the day of injection. Methotrexate was
given as methotrexate sodium.
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Histopathologic examination of the enucleated eyes showed no photoreceptor
or ganglion cell layer damage in the experimental eyes compared with the control,
away from the site of injection (Figure 3). The optic nerve and medullary rays appeared intact in both the
treated and control eyes.
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Figure 3. Light microscopy of an experimental
eye shows intact retinal layers with no cellular atrophy or disorganization
(hematoxylin-eosin, original magnification x40). The retinal detachment
is an artifact.
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COMMENT
A cycle of intravitreal injections of methotrexate, fluorouracil, and
dexamethasone was developed for the treatment of intraocular malignancy such
as PIOL. The dosing interval selected for serial methotrexate injections will
deliver therapeutic drug levels in the vitreous for 8 days. This protracted
exposure of lymphoma cells to methotrexate would allow most of the tumor cells
that are active in the cell cycle to pass through the S phase and be exposed
to the drug. Antineoplastic synergism is enhanced when methotrexate levels
are at least 10µM and fluorouracil is given 24 hours after methotrexate
exposure.43 According to equation 1, the concentration
of methotrexate in the vitreous is 46µM 24 hours after the methotrexate
injection; therefore, a fluorouracil injection on day 2 of the cycle would
be appropriate. Dexamethasone is given at the end of the cycle to potentially
treat cells not progressing through the S phase. Corticosteroid application
at the end of a cycle may also be useful in treating an inflammatory response
secondary to tumor cell death.
The rabbit eye is commonly used to study the pharmacokinetics of drugs
injected into the eye. However, several factors must be considered when interpreting
these pharmacokinetic data. First, the development of the treatment schedule
in Table 1 assumes that the injections
of fluorouracil and dexamethasone do not affect the clearance of methotrexate
from the eye. The drugs were not dosed simultaneously but rather on a staggered
schedule separated by at least 24 hours. Therefore, the effect of fluorouracil
and dexamethasone injections on the clearance of methotrexate would not likely
be as large a concern as with concomitant dosing. If the clearance of methotrexate
were delayed by fluorouracil, the methotrexate concentration in the vitreous
would be increased. Therefore, therapeutic levels of methotrexate would be
present at the time of fluorouracil injection as predicted by part 1 of our
study, and the dosing and sequence of drugs in our treatment schedule would
remain the same. A larger concern with delayed methotrexate clearance would
be an increased potential for ocular toxic effects. However, part 2 of this
study showed no drug toxic effects when the sequence of drugs in Table 1 was used at twice the dose and
throughout 3 cycles.
Second, patients with PIOL often have had previous cataract surgical
procedures and vitrectomies. One can expect the clearance of small-molecular-weight
drugs to be faster in aphakic and/or vitrectomized eyes.44
This, however, was not examined in this study.
Third, pharmacokinetic data reported for other drugs in rabbit eyes
have shown intraocular drug accumulation in the vitreous of the fellow eye
following an intravitreal injection in the opposite eye,45
presumably from an intercommunicating vessel,46
raising a concern regarding the independence of the right and left eye during
intravitreal treatment. However, in previous experiments (Michael R. Robinson,
MD, unpublished data, 1998), no detection of methotrexate was found in the
fellow eye following intravitreal administration of methotrexate in the opposite
eye.
Finally, the rabbit eye differs from the human eye in volume and surface
area for drug clearance. It would be useful to extrapolate the pharmacokinetic
measurements describing methotrexate clearance from the rabbit eye to the
human eye to obtain estimates of the dosages and dosing intervals required
to maintain a therapeutic level. The volume (V) of
the human eye is 3.9 mL compared with the rabbit's eye of 1.5 mL. When chemotherapeutic
agents are dosed systemically, clearance (CL) scales allometrically according
to body surface area. By assuming that a similar principle applies to intravitreal
dosing, an estimate of the CL of methotrexate from the human eye might be
obtained as follows:
By using vitreous volumes for the scaling, CL from the human eye is
estimated to be 0.38 mL/h. If the volume of distribution is 47% higher than
the vitreous volume, as it was in the rabbit, the corresponding half-life
is estimated to be 10.4 hours. The equation describing methotrexate concentration
after injection would be as follows:
where C indicates concentration; exp, exponential;
and t, time.
In Figure 4, we used equation
3 to predict methotrexate concentrations over time in a human eye following
a 400-µg injection. Methotrexate levels of more than 0.5 µM are
predicted throughout the cycle, and the drug level at 24 hours (31.9 µM)
is adequate for the antineoplastic synergy with fluorouracil.
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Figure 4. Predicted kinetics of methotrexate
in the vitreous following 400-µg injection into human eyes on days 1,
4, and 6.
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Ethical issues restrain investigators from conducting similar pharmacokinetic
studies in human eyes. However, a treatment schedule based on the literature
and the data presented herein could be safe and potentially effective for
the treatment of primary intraocular lymphoma in humans. A pilot study at
the National Eye Institute, Bethesda, Md, in conjunction with the National
Cancer Institute, Bethesda, is being developed to examine the safety and efficacy
of this regimen in patients with PIOL.
AUTHOR INFORMATION
Accepted for publication March 8, 2001.
Corresponding author and reprints: Gisela Velez, MD, MPH, 85 Washington
Park, Newton, MA 02460 (e-mail: brusie-velez{at}erols.com).
From the Laboratory of Immunology, National Eye Institute (Drs Velez,
Chan, and Nussenblatt), Pharmacy Department, Clinical Center (Dr Yuan), Bioengineering
and Physical Sciences Program, Office of the Director (Dr Sung), Veterinary
Research and Resources Section, National Eye Institute (Dr Tansey), and Division
of Epidemiology and Clinical Research, National Eye Institute (Drs Reed and
Robinson), National Institutes of Health, Bethesda, Md. Dr Velez is now with
the Massachusetts Eye and Ear Infirmary, Boston, and Retina Specialists of
Boston.
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