Download oral cyclosporine use in dogs

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Focus on Pharmacology
ORAL CYCLOSPORINE
USE IN DOGS
Todd M. Archer, DVM, MS, Diplomate ACVIM
Andrew Mackin, BVMS, DVSc, Diplomate ACVIM
Mississippi State University
Originally derived from a soil fungus, cyclosporine
is a powerful immunosuppressive drug that was
initially used in humans to prevent rejection of
transplanted organs.1-3
In 2003, oral cyclosporine capsules (Atopica,
novartis.com) received Food and Drug Administration
(FDA) approval for treatment of atopy in dogs.
Extralabel use of cyclosporine includes:
• Treatment of a variety of inflammatory and
immune-mediated conditions
• Immunosuppressive action for renal
transplantation in dogs and cats.
ORAL FORMULATIONS
Commercial cyclosporine is available as 2 different
oral formulations: Cyclosporine was initially
developed as a vegetable oil-based preparation
(Sandimmune, novartis.com), but this formulation
has very poor oral bioavailability and is not
recommended for oral use in dogs.
A subsequent ultramicronized preparation—
FDA approved in 1996 (Neoral, novartis.com)—
has much more consistent and predictable
bioavailability. Atopica, the veterinary equivalent of
the Neoral microemulsion preparation, is approved
for use in dogs and cats.
MECHANISM OF ACTION
The main mechanism of action of cyclosporine is
inhibition of T-lymphocyte function. Cyclosporine
inhibits the intracellular enzyme calcineurin.
Calcineurin inhibitors, including cyclosporine,
act by binding to intracellular cyclophilins, which
then inhibit calcineurin-mediated production
of cytokines, such as IL-2. Because IL-2 plays
a key role in the activation and proliferation of
T-lymphocytes, inhibition of IL-2 production
causes blunting of the immune response.
PHARMACOKINETICS
Absorption
After oral administration, cyclosporine is absorbed
through the small intestinal epithelium. A decrease
in oral bioavailability was reported when the
veterinary formulation was administered with food
to dogs, which led to recommendations that the
drug should be administered 2 hours before or
after feeding.4,5
TABLE 1.
Important Drugs That Affect Cyclosporine Concentrations in Blood
DRUG TYPE
MAY INCREASE
CYCLOSPORINE CONCENTRATION
MAY DECREASE
CYCLOSPORINE CONCENTRATION
Antibacterials
Azithromycin
Chloramphenicol
Ciprofloxacin
Clarithromycin
Enrofloxacin
Erythromycin
Imipenem
Metronidazole
Clindamycin
Sulfadiazine
Trimethoprim
Antifungals
Fluconazole
Itraconazole
Ketoconazole
Terbinafine
Gastroprokinetics
Gastroprotectants
Cimetidine
Cisapride
Metoclopramide
Omeprazole
Famotidine
Other Drugs
Calcium channel blockers
Digoxin (cardiac glycoside)
Estrogens (hormone)
Flavonoids in grapefruit juice
Azathioprine (immunosuppressive)
Phenobarbital (anticonvulsant)
Phenytoin (anticonvulsant)
Cyclophosphamide (chemotherapeutic)
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Distribution
Once cyclosporine reaches systemic circulation,
it distributes widely but accumulates in the
skin, kidneys, liver, and fat of dogs.6 Peak blood
concentration in dogs generally occurs about 2
hours after oral administration of the veterinary
formulation, with a rapid decrease in blood
concentrations then occurring over the remainder
of the dosing interval.
Metabolism
Metabolism of cyclosporine occurs in the small
intestine, kidneys and, particularly, liver. In dogs,
hepatic cytochrome P-450 3A provides the key
metabolic pathway. A number of drugs can alter
cyclosporine metabolism by affecting the hepatic
P-450 enzyme system (Table 1, page 105).
In dogs, different drugs have been administered
concurrently with cyclosporine in order to reduce
the amount of cyclosporine needed to maintain
adequate blood drug concentrations. The most
common drug administered with cyclosporine is
ketoconazole, an antifungal agent shown to allow a
decrease in the dosage of oral cyclosporine in dogs
by as much as 75%.7
Excretion
Excretion occurs primarily through the biliary
system with minimal renal excretion.1,8,9
ADVERSE EFFECTS
The most notable adverse effects associated with
oral cyclosporine are gastrointestinal, including
diarrhea, vomiting/nausea, and anorexia; Table 2
lists side effects seen in dogs. Myelosuppression
and neutropenia are possible adverse effects common
to most other immunosuppressive agents, but these
have not been reported with cyclosporine use in dogs.
Concurrent infections have been documented
in patients receiving cyclosporine therapy, and
lymphoma has occurred in conjunction
with use of cyclosporine.10
TABLE 2.
PRECAUTIONS
The safety and efficacy of cyclosporine
has not been established in dogs less
than 4 pounds in weight or less than
6 months of age; it should be avoided
or only used cautiously in these
patients. Although nephrotoxicity
has not been reported in dogs
receiving standard therapeutic doses,
cyclosporine should be used cautiously
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in patients with renal failure.
Cyclosporine could potentially impact vaccine
efficacy due to its ability to dampen the immune
system.11 Vaccine approval studies utilizing a
killed rabies vaccine have documented adequate
antibody titer responses in dogs even when
high cyclosporine doses were administered.
While vaccine efficacy has been documented
in humans receiving cyclosporine,12,13 similar
studies are not available in dogs. Therefore, solid
recommendations are not available.
THERAPEUTIC DRUG MONITORING
Due to the highly variable nature of absorption
and metabolism of cyclosporine in dogs,
monitoring cyclosporine blood concentrations may
help facilitate successful therapeutic management.
Unfortunately, the process of adjusting drug
doses based on monitoring cyclosporine blood
concentrations is clinically complex.
Measurement Methods
The method utilized to measure cyclosporine
blood concentrations must be taken into account
when interpreting results. Currently available
methods for measuring cyclosporine blood
concentrations include:
• High performance liquid chromatography (HPLC)
• Specific monoclonal radioimmunoassay (RIA).
HPLC is considered the gold standard for
measuring cyclosporine blood concentrations,
and can distinguish the parent drug from its
metabolites. It is often only used for research
purposes rather than routine patient monitoring.
In contrast, RIA measures the metabolites
as well as the parent drug without distinction.
Therefore, blood cyclosporine concentrations will
be higher by a factor of 1.5 to 1.7 compared with
the same sample analyzed using HPLC.4 RIA
is the method most often employed for clinical
Important Adverse Effects Reported in Dogs
Receiving Oral Cyclosporine
Common
Anorexia
Diarrhea
Vomiting
Less
Common
Anaphylactic reaction
Angioedema
Coat shedding
Emergence of neoplasia
Gingival hyperplasia
Hepatotoxicity
Hirsutism
Hyperkeratosis of the footpads
Lameness
Lethargy
Nephropathy
Papillomatosis
Secondary infections
Tremors
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patients and the laboratory performing the assay
typically provides their therapeutic ranges.
Sample Collection
Sample type and timing of collection also influence
interpretation of cyclosporine concentrations. Most
laboratories recommend:
• Measuring whole blood concentrations of
cyclosporine
• Submitting trough and peak blood samples (by
collecting them before administration of the next
dose and 2 hours post dosing, respectively) in
the early phases of treatment.
Currently, the main veterinary laboratory in the
U.S. handling clinical samples for cyclosporine
blood concentrations, and providing therapeutic
ranges, is the Auburn University Clinical
Pharmacology Lab (vetmed.auburn.edu/clinical
-pharmacology-lab).
Peer Reviewed
have confirmed that an initial starting dosage of 5
mg/kg PO Q 24 H helps successfully manage the
majority of dogs with atopy.15–17 Therapeutic drug
monitoring of cyclosporine in dogs being treated for
atopy is not typically recommended.
PHARMACODYNAMIC MONITORING
Pharmacodynamic assays, which investigate the
drug’s effect on target cells, have been extensively
studied in human medicine. At Mississippi State
University, research14 evaluating T-cell responses
to cyclosporine—in normal dogs as well as
clinical patients—has confirmed that canine
responses are comparable to those seen in people.
This assay is now offered nationally for use by
veterinarians to help determine dosage needs for
individual patients. More information can be
obtained at cvm.msstate.edu/animal-health-center/
pharmacodynamic-laboratory.
Anal Furunculosis
Anal furunculosis is a chronic inflammatory disease
in dogs that causes focal to multifocal ulcerative
tracts within perianal tissues.9 Oral cyclosporine
has been shown in multiple studies to be effective
for treatment of anal furunculosis in most dogs at a
typical starting dosage of 4 to 8 mg/kg PO Q 12
H or Q 24 H.9 Measurement of blood cyclosporine
concentrations is not typically recommended during
therapy, but instead, drug doses should be titrated
based on resolution of clinical disease and lack of
signs of toxicity (eg, anorexia, depression).9
Studies have documented that combining
ketoconazole with cyclosporine therapy can reduce
the cost of therapy, while achieving control of
anal furunculosis.9,18 Ketoconazole is often used
at a dosage of 5 to 10 mg/kg PO Q 24 H in
combination with lower doses of cyclosporine
(most studies have evaluated cyclosporine at an
oral dosage of 1 to 2 mg/kg PO Q 12 H in
combination with ketoconazole).
When combining ketoconazole and
cyclosporine, therapeutic drug monitoring is
recommended to ensure that adequate cyclosporine
concentrations are being attained; appropriate
monitoring for ketoconazole hepatotoxicity also
should be performed.
SPECIFIC DISEASE
CONSIDERATIONS (Table 3)
Atopic Dermatitis
Atopic dermatitis is common in dogs and associated
with IgE antibodies that target environmental
allergens.15 Atopy is the only condition in dogs for
which Atopica is FDA approved. Multiple studies
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is one of the
most common chronic gastrointestinal diseases
in dogs, with clinical signs often including
vomiting, diarrhea, and weight loss.19 Cyclosporine
has been shown to be effective as a sole drug
therapy for IBD in most dogs.20 We typically
TABLE 3.
Cyclosporine Use for Specific Diseases
DISEASE
CYCLOSPORINE DOSAGE
THERAPEUTIC MONITORING
Atopic Dermatitis
Starting dosage, 5 mg/kg PO Q 24 H
Not typically recommended
Anal Furunculosis
*4–8 mg/kg PO Q 12 H or 24 H
Not typically recommended
Cyclosporine,*1–2 mg/kg PO Q 12 H
Ketoconazole, 5–10 mg/kg PO Q 24 H
Recommended
IBD
5 mg/kg PO Q 12 H or 24 H*
Not typically recommended
IMHA; IMT
Starting dosage, 7.5–10 mg/kg PO Q 12 H*
Recommended
* Extralabel use
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Overview of Clinical Use of Cyclosporine
Individual responses to cyclosporine
are quite variable, both in dogs
receiving the same standard oral dose
as well as in dogs with oral doses
adjusted to attain comparable blood
concentrations. Given this high degree
of variability, cyclosporine dosing
protocols should be tailored to the
individual dog.
Dosing & Monitoring Protocols
In our opinion, canine dosing protocols
of oral cyclosporine for the treatment
of non–life-threatening skin and
gastrointestinal diseases should be
quite different from protocols used
in patients with more acute and
life-threatening immune-mediated
diseases.
In diseases that are not typically
immediately life-threatening, such
as atopy, anal furunculosis, and mild
IBD, cyclosporine is often effective
when initiated at a standard lower
starting dose. Drug doses can be
adjusted upwards if needed, based
predominantly on clinical signs. Longterm cyclosporine therapy is tapered
to the lowest effective dose needed to
maintain remission.
Measurement of cyclosporine
blood concentrations is usually not
indicated in these circumstances,
as remission of disease is the main
criterion used to determine whether
adequate therapy is being delivered.
However, if there is refractory disease
that is not responding to typical
cyclosporine therapy, measuring blood
concentrations may be considered
as the disposition of cyclosporine in
the individual patient can be quite
variable.
Since recent pharmacodynamic
studies showed that some dogs can
have significant suppression of T-cell
biomarkers when administered low
dosages of cyclosporine,14 clinicians
should remain vigilant for signs of
systemic infection.
In dogs being treated for
more acute and life-threatening
diseases, such as IMHA and
IMT, cyclosporine therapy must
be utilized to attain effective
immunosuppression as quickly
as possible. To ensure adequate
immunosuppression and proper
treatment, measuring blood
cyclosporine concentrations and/or
begin cyclosporine therapy at 5 mg/kg PO Q
12 H or 24 H for treatment of IBD. Measuring
cyclosporine blood concentrations in dogs being
treated for IBD is not typically recommended.
Immune-Mediated Hemolytic Anemia &
Immune-Mediated Thrombocytopenia
Immune-mediated hemolytic anemia (IMHA)
and immune-mediated thrombocytopenia (IMT)
are life-threatening blood disorders that often
require significant immunosuppression to attain
disease remission. Cyclosporine can be utilized for
treatment of both IMHA and IMT.
Cyclosporine is typically initially dosed
between 7.5 to 10 mg/kg PO Q 12 H, with
measurement of cyclosporine blood concentrations
employed to ensure adequate immunosuppression.
Unfortunately, for both of these diseases, an
insufficient number of cases have been published to
assess response to cyclosporine therapy.
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Generic Formulations
Cyclosporine is expensive, which
tempts clinicians to explore cheaper
forms of the drug. In human medicine,
there are many generic microemulsion
preparations similar to Neoral, and
these preparations are shown to have
therapeutic equivalency. Similar studies
have not been performed in dogs, but
a single published study reported that
generic cyclosporine was effective in
reducing the severity of clinical signs
of canine atopic dermatitis, although
blood drug concentrations were not
evaluated.21
In our experience, there appears
to be marked variability in the oral
bioavailability of generic products
in individual dogs. Use of generic
products, particularly in patients with
life-threatening disease, can, therefore,
place our patients at risk of therapeutic
failure. In our opinion, the FDAapproved veterinary product remains
the preferred cyclosporine formulation
for use in dogs.
agent used to treat a variety of diseases. Significant
variations in absorption and clinical efficacy can
be seen between patients. With life-threatening
immune-mediated diseases, higher dosages
of cyclosporine are often utilized, along with
therapeutic drug monitoring to ensure that
adequate blood concentrations are achieved. With
milder diseases, such as atopy, cyclosporine is
usually administered at the recommended dosages,
with individual treatment responses used to
determine subsequent dose adjustments.
FDA = Food and Drug Administration; HPLC
= high performance liquid chromatography;
IBD = inflammatory bowel disease; IMHA =
immune-mediated hemolytic anemia; IMT =
immune-mediated thrombocytopenia; RIA =
radioimmunoassay
References
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IN SUMMARY
In dogs, cyclosporine is an immunosuppressive
performing pharmacodynamic testing
is strongly recommended in patients
with life-threatening diseases.
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TODD M. ARCHER
ANDREW MACKIN
Thomas SE, et al. Immune
Todd M. Archer, DVM, MS, Diplomate
Andrew Mackin, BVMS, DVSc, Diplomate
response to rabies vaccination
ACVIM, is assistant professor of small
ACVIM, is professor and interim head
in pediatric transplant patients.
animal medicine in the Department
in the Department of Clinical Sciences
Pediatr Transplant 2008;
of Clinical Sciences at Mississippi
at Mississippi State University College
12(8):874-877.
Archer TM, Fellman CL, Stokes
State University College of Veterinary
of Veterinary Medicine. He received his
JV, et al. Pharmacodynamic
Medicine. He received his DVM and
BVMS at Murdoch University in Australia,
monitoring of canine T-cell
completed an internship and residency
completed a residency in small animal
cytokine responses to oral
at Mississippi State University. His
medicine at University of Melbourne,
cyclosporine. J Vet Intern Med
research has primarily focused on T-cell
and completed an internal medicine residency at Ontario
2011; 25(6):1391-1397.
responses in dogs to cyclosporine using
Veterinary College. His research is focused on hematology,
Olivry T, DeBoer DJ, Favrot
both flow cytometry and qRT-PCR.
immunosuppressive therapy, and transfusion medicine.
C, et al. Treatment of canine
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