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Focus on Pharmacology
Oral Cyclosporine Use in Dogs

Focus on Pharmacology</br>Oral Cyclosporine Use in Dogs

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Todd Archer, DVM, MS, Diplomate ACVIM, and Andrew Mackin, BSc, BVMS, 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

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).

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

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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

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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 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 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).

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.

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 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.

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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.

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 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.

IN SUMMARY

In dogs, cyclosporine is an immunosuppressive 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

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. Long-term 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 performing pharmacodynamic testing is strongly recommended in patients with life-threatening diseases.

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 FDA-approved veterinary product remains the preferred cyclosporine formulation for use in dogs.

References

  1. Tedesco D, Haragsim L. Cyclosporine: A review. J Transplant 2012; 2012:230386.
  2. Kahan BD. Therapeutic drug monitoring of cyclosporine: 20 years of progress. Transplant Proc 2004; 36(2 Suppl):378S-391S.
  3. Calne R. Cyclosporine as a milestone in immunosuppression. Transplant Proc 2004; 36(2 Suppl):13S-15S.
  4. Steffan J, Strehlau G, Maurer M, Rohlfs A. Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs. J Vet Pharmacol Ther 2004; 27(4):231-238.
  5. Guaguere E, Steffan J, Olivry T. Cyclosporin A: A new drug in the field of canine dermatology. Vet Dermatol 2004; 15(2):61-74.
  6. Robson D. Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in people, dogs and cats. Vet Rec 2003; 152(24):739-748.
  7. Dahlinger J, Gregory C, Bea J. Effect of ketoconazole on cyclosporine dose in healthy dogs. Vet Surg 1998; 27(1):64-68.
  8. Plumb DC. Plumb’s Veterinary Drug Handbook, 6th ed. PharmaVet Inc, 2008, p 5.
  9. Patterson AP, Campbell KL. Managing anal furunculosis in dogs. Compend Pract Vet Small Anim Pract 2005:339-355.
  10. Blackwood L, German AJ, Stell AJ, O’Neill T. Multicentric lymphoma in a dog after cyclosporine therapy. J Small Anim Pract 2004; 45(5):259-262.
  11. Thacker EL. Immunomodulators, immunostimulants, and immunotherapies in small animal veterinary medicine. Vet Clin North Am Small Anim Pract 2010; 40(3):473-483.
  12. Rodriguez-Romo R, Morales-Buenrostro LE, Lecuona L, et al. Immune response after rabies vaccine in a kidney transplant recipient. Transpl Infect Dis 2011; 13(5):492-495.
  13. Cramer CH II, Shieck V, Thomas SE, et al. Immune response to rabies vaccination in pediatric transplant patients. Pediatr Transplant 2008; 12(8):874-877.
  14. Archer TM, Fellman CL, Stokes JV, et al. Pharmacodynamic monitoring of canine T-cell cytokine responses to oral cyclosporine. J Vet Intern Med 2011; 25(6):1391-1397.
  15. Olivry T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 2010; 21(3):233-248.
  16. Steffan J, Seewald W. Clinical trial evaluating the efficacy and safety of cyclosporine in dogs with atopic dermatitis. JAVMA 2005; 226:1855-1863.
  17. Olivry T, Steffan J, Fisch R, et al. Randomized controlled trial of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs. JAVMA 2002; 221:370-377.
  18. Patricelli AJ, Hardie RJ, McAnulty JF. Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. JAVMA 2002; 220:1009-1016.
  19. Fogle JE, Bissett SA. Mucosal immunity and chronic idiopathic enteropathies in dogs. Compend Contin Educ Pract Vet 2007; 29(5):290-302; quiz 306.
  20. Allenspach K, Rufenacht S, Sauter S, et al. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. J Vet Intern Med 2006; 20(2):239-244.
  21. Kovalik M, Taszkun I, Pomorski Z, et al. Evaluation of a human generic formulation of ciclosporin in the treatment of canine atopic dermatitis with in vitro assessment of the functional capacity of phagocytic cells. Vet Rec 2011; 168(20):537.

Todd M. ArcherTodd M. Archer, DVM, MS, Diplomate ACVIM, is assistant professor of small animal medicine in the Department of Clinical Sciences at Mississippi State University College of Veterinary Medicine. He received his DVM and completed an internship and residency at Mississippi State University. His research has primarily focused on T-cell responses in dogs to cyclosporine using both flow cytometry and qRT-PCR.

 

 

Andrew MackinAndrew Mackin, BVMS, DVSc, Diplomate ACVIM, is professor and interim head in the Department of Clinical Sciences at Mississippi State University College of Veterinary Medicine. He received his BVMS at Murdoch University in Australia, completed a residency in small animal medicine at University of Melbourne, and completed an internal medicine residency at Ontario Veterinary College. His research is focused on hematology, immunosuppressive therapy, and transfusion medicine.

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