Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 12 IMMUNOMODULATORY THERAPY
Formulations and dose rates—cont’d
Sandimmun®, there is no such recommendation listed on the data
sheet for Neoral® as this formulation has more predictable pharmacokinetics
with a higher safety margin. Monitoring may be considered
when ciclosporin is administered concurrently with ketoconazole (see
below). The dose rate of ciclosporin should be gradually tapered as
for other immunosuppressive medicines. For Neoral® administered
for the control of chronic atopic dermatitis in dogs, the recommendation
is for daily administration (as above) until there is clinical improvement.
This will normally occur within 4 weeks of therapy and if there
has been no response within 8 weeks, treatment should be stopped.
Following control of clinical signs, Neoral® may be given every other
day, then every 3–4 days and fi nally withdrawn. Recurrence of clinical
signs following withdrawal of therapy requires reinstigation of daily
dosing. This dosage regimen has now become reasonably standard
for most applications of Neoral® but earlier literature on the use of
ciclosporin A (often as Sandimmun®) may report a range of different
dosage regimens for oral or intravenous administration.
Ciclosporin has been administered concurrently with prednisolone
to achieve immunosuppression in diseases such as canine IMHA and
in this instance should be gradually tapered in conjunction with reduction
in the dosage of glucocorticoid. Current data sheet recommendations
for Neoral® are, however, that this agent not be administered
concurrently with other immunosuppressives.
In the medical management of canine anal furunculosis, reduced
dosage of ciclosporin has been achieved by concurrent administration
of ketoconazole (see below) which competitively inhibits enzymes
involved in ciclosporin metabolism (e.g. cytochrome P450). Increased
bioavailability occurs when grapefruit juice is administered concurrently
with oral ciclosporin (Sandimmun®). However, as dogs and
cats are unlikely to imbibe much, if any, grapefruit (or any other) juice,
this is unlikely to be of clinical relevance in veterinary practice.
Optimmune® is administered to the conjunctival sac by applying
a small quantity of ointment (0.5–1.0 cm) q.12 h. Lifelong therapy
may be required for KCS and continuous therapy is required to stimulate
tear production, which may not be evident for 2–6 weeks. Adjunct
treatment (e.g. tear replacement) is also generally administered
during the initial phases of treatment. In the treatment of pannus,
intermittent therapy may be appropriate, with reduced frequency of
application possible during periods of reduced exposure to UV light.
Tacrolimus is formulated as an ointment for topical application in
the treatment of human atopic dermatitis (Protopic® 0.1% tacrolimus
ointment; Fujisawa Healthcare). There is minimal systemic absorption
and thus a low risk of adverse effects. Protopic® has been used to
effectively treat dogs with atopic dermatitis, particularly cases with
localized disease.
Pharmacokinetics
Pharmacokinetic studies of the original ciclosporin formulation,
Sandimmun®, administered to dogs revealed
that peak concentrations were generally achieved 2–4 h
after oral administration, with only 20–25% of the dose
absorbed and substantial variation between dogs. This
low bioavailability may increase with longer duration
of dosing. The bioavailability of Neoral® is higher, at
approximately 35%, as a result of improved micellar
formulation. While bile salts are required to emulsify
Sandimmun® there is no effect of bile salts on Neoral®
absorption. The absorption of Neoral® is impaired by
ingestion of fatty meals within 30 min of administration,
leading to the recommendation not to administer
Neoral® within 2 h of feeding. Absorbed ciclosporin
has high affinity for plasma lipoproteins, but up to 50%
of absorbed drug is located within erythrocytes and
leukocytes. Highest tissue concentrations occur in fat
and the liver, with lower concentrations in pancreas,
kidneys, skin and heart. Metabolism is extensive and
carried out by the cytochrome P450 microsomal enzyme
system. Metabolites are largely excreted in bile, with
some minor (5%) urinary loss.
Adverse effects
● The immunosuppressive effects of ciclosporin have
the potential to result in secondary infection or
malignancy (particularly lymphoid). The dog and cat
appear relatively tolerant of the drug but isolated
cases of recrudescence of existing infection or development
of primary infection have been recorded in
both species. Ciclosporin should not be used in
animals with pre-existing neoplastic disease.
● In the cat the major reported side effect is soft
feces.
● In dogs a range of adverse effects has been recorded.
The most common are vomiting, diarrhea or soft
feces. These effects are mild and transient and do not
warrant withdrawal of therapy. Other effects include:
anorexia, gingival hyperplasia, papillomatosis, hirsutism,
hair shedding, red and swollen ears, muscle
weakness or muscle cramps. These signs rapidly
resolve on withdrawal of the drug.
● Renal toxicity is rarely reported, except with high
dose rates, which may also induce defective hepatic
protein synthesis, inhibition of insulin release and
peripheral insulin resistance. Ciclosporin should
therefore be used with particular care in diabetic
dogs and dogs with renal disease should be closely
monitored (e.g. via serum biochemistry).
● Ciclosporin (or its excipients) may induce hypersensitivity
and the drug should not be administered to
animals that are sensitized. This particularly applies
to the injectable products which contain Cremophor
as a solubilizing agent.
● Ciclosporin should not be administered to pregnant
or lactating animals as it may cross the placental
barrier and pass into the milk. The safety of the drug
has not been studied in breeding male dogs.
● Ciclosporin is not recommended for use in dogs
under 6 months of age or those that weigh less than
2 kg.
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