Portal de Periódicos da CAPES

More Economical Use of Cyclosporine Through Combination Drug Therapy

2002; American Animal Hospital Association; Volume: 38; Issue: 3 Linguagem: Inglês

10.5326/0380205

1547-3317

Jenise Coyne Daigle,

Drug-Induced Adverse Reactions

Cyclosporine (CyA), a secreted fungal polypeptide discovered in 1972, has profound immunosuppressant properties in vitro and in vivo1 and has been used clinically to inhibit rejection of transplanted organs. More recently, because of its unique immunomodulating properties, CyA has been used in humans for the treatment of chronic asthma, membranous glomerulonephropathy, immune-mediated thrombocytopenia in children, atopic dermatitis, psoriasis, lichen planus, and many other inflammatory dermatoses.2–5Cyclosporine is gaining wide use in veterinary medicine. In cats, CyA administration has successfully prolonged acceptance of renal allografts.6 Cyclosporine has been used successfully for the treatment of dogs with refractory immune-mediated anemia and immune-mediated thrombocytopenia.7 Cyclosporine is also available in an ophthalmic preparation for the control of keratoconjuctivitis sicca in dogs.a Recently, CyA has also been indicated for the treatment of dogs with perianal fistulas and atopic dermatitis.89Cyclosporine is currently marketed in two oral formulations.b,c The original formulationb was introduced in 1983. The product was reformulated in 1996 as a microemulsion concentratec that is absorbed more rapidly and completely.10 The microemulsion concentrate is directly absorbed through the gut epithelium and appears to be minimally affected by biliary diversion, gastrointestinal motility, and concomitant food intake—all of which affected the bioavailability of the original formulation of CyA in humans.10 The microemulsion formulation of CyA has a faster rate of absorption, greater efficacy, and greater bioavailability in humans.1112 However, the microemulsion formulation is more expensive than the original formulation.Cyclosporine has low cytotoxicity relative to its immunosuppressive properties. Cyclosporine becomes active by binding to cyclophilin, a specific intracellular receptor. This leads to inhibition of three calcium-dependent pathways: exocytosis, apoptosis, and the enzymatic actions of calcineurin. Inhibition of calcineurin results in the blockade of interleukin (IL)-2 transcription. The blocking of IL-2 transcription leads to impaired T-helper and T-cytotoxic lymphocytes. Cyclosporine also inhibits transcription of alpha-interferon, a cytokine that provides amplification signals for macrophage and monocyte activation.13 The production of other cytokines (including IL-3, IL-4, IL-5, tumor necrosis factor alpha, and gamma interferon) may be impaired, thus indirectly inhibiting antigen presentation, mononuclear cell function, mast cell and eosinophil production, histamine and prostaglandin release from mast cells, neutrophil adherence, natural killer-cell activity, and growth and differentiation of B cells.13Cyclosporine is extensively metabolized in the liver by the cytochrome P-450 liver microsomal enzymes, with demethylation and hydroxylation being the major pathways of metabolism.1415 Drugs which inhibit the hepatic microsomal enzymes will alter the clearance of CyA and hence cause blood levels of CyA to increase with continued administration. Ketoconazole is known to bind to some of the isoenzymes of the P-450 system with resultant inhibition of the metabolism of drugs that are metabolized by the cytochrome P-450 system. Ketoconazole has been shown to have the effect of increasing blood CyA levels when coad-ministered with CyA and has been used in the clinical setting in order to reduce the dosage and cost of CyA.24 With concurrent ketoconazole (13.6 mg/kg body weight per day) administration, the CyA dose decreased from 14.5 mg/kg body weight per day to 3.4 mg/kg body weight per day, representing a 75% reduction in CyA dose, which resulted in a monetary savings of 58% per month.2 Administering a lower dose of ketoconazole (4.7 mg/kg body weight per day), the CyA dose decreased from 14.5 mg/kg per day to 10.1 mg/kg per day, representing a 38% reduction in CyA dose, which resulted in a monetary savings of 23.8% per month.2 As an example presented in US dollars, to treat a 20-kg dog with 5 mg/kg body weight per day of the microemulsion formulation, it would cost approximately $6.75 per day. The dose of CyA can be reduced by half by adding in generic ketoconazole at 5 mg/kg body weight per day (approximately $0.50 for half of a 200-mg ketoconazole tablet), which will decrease the cost of CyA to $3.87 a day.Other drugs in humans that have been proposed to increase CyA levels by inhibition of the cytochrome P-450 liver microsomal enzymes include the following: itraconazole, fluconazole, cimetidine, diltiazem, erythromycin, doxycycline, metoclopramide, methylprenisolone, and flavonoids in grapefruit juice.15 Unfortunately, the only drug that has been researched for use with CyA in veterinary patients to date is cimetidine. In a recent study, cimetidine was found to have no effect on the clearance nor to lead to an overall increase in blood CyA levels.16 Inducers of cytochrome P-450 isoenzymes, including phenobarbital and rifampin, are reported to decrease CyA blood concentrations presumably through increased metabolism, and they should be avoided when possible.16Side effects reported with CyA in dogs include gastrointestinal (e.g., vomiting, diarrhea, anorexia), weight loss, gingival hyperplasia, papillomatosis, hypertrichosis, and excessive shedding, with gastrointestinal side effects being the most common.8 Cats are reported to have only minor side effects, with soft feces being most commonly reported.17 Contrary to the situation in humans, CyA is not nephrotoxic or hepatotoxic in dogs and cats unless extremely high blood concentrations (>3,000 ng/mL) are maintained.18 Inappetence in cats can be associated with blood levels >1,000 ng/mL.18 Lymphoproliferative disorders and lymphoma have been associated with prolonged CyA usage in humans and cats.19The combination of CyA and ketoconazole has not resulted in an increase of reported side effects.2420 Gastrointestinal symptoms of vomiting, diarrhea, or anorexia are the most common adverse effects seen with ketoconazole therapy alone. Hepatic toxicity consisting of cholangiohepatitis and increased liver enzymes has been reported with ketoconazole and may be either idiosyncratic in nature or a dose-related phenomenon. Cats may be more prone to developing hepatoxicity than dogs.21 Ketoconazole and CyA combination therapy is best avoided in patients with preexisting liver disease. When ketoconazole therapy will continue for months at a time, liver enzymes and complete blood counts should be regularly monitored. This is not necessary when medication is used for only a few weeks.Unfortunately, limited veterinary studies have addressed therapeutic CyA concentrations. The therapeutic range has principally evolved from organ transplant work in dogs and cats. To achieve immunosuppression in dogs, a 12-hour whole blood trough level (measured just before the next oral dose) of at least 500 ng/mL is recommended.18 In cats, a 12-hour whole blood trough level of 250 ng/mL to 500 ng/mL is recommended.18A common oral dose in humans is 5 to 10 mg/kg body weight per day to achieve targeted whole blood concentrations of 150 to 400 ng/mL.3 In humans, dosages are adjusted to meet the needs of the individual patient based on clinical response and monitoring trough plasma concentrations. For animals, doses of 10 to 20 mg/kg body weight per day were frequently cited in the literature, but more recent publications, documenting newer formulations that have been used, have cited lower doses. For organ transplantation in cats, a dose of 3 mg/kg body weight q 12 hours was used to achieve blood concentrations of 300 to 500 ng/mL.18 For organ transplant in dogs, 10 mg/kg body weight q 12 hours has been given to achieve concentrations of 500 to 600 ng/mL.18There is wide individual variation in CyA pharmacokinetics; therefore, monitoring can be used to determine the optimum dose for each patient. One must be aware of the assay used when monitoring CyA. Whole blood or plasma levels of CyA can be measured by high-pressure liquid chromatography (HPLC), fluorescence polarization immunoassay, and specific monoclonal antibody radioimmunoassay. Plasma values will be lower than whole blood assays, because as much as 50% to 60% and 10% to 20% of the dose is concentrated in erythrocytes and leukocytes, respectively. Nonspecific assays will report higher values than a more specific (e.g., monoclonal or HPLC) assay.2122Orally administered CyA is effective in severe cases of atopic dermatitis in humans and dogs.23–25 Anecdotal reports of successful use of CyA in refractory atopic cats have also been noted. In one study, CyA monotherapy proved to be very beneficial in 13 of 14 dogs with severe atopic dermatitis at a dosage of 10 to 20 mg/kg body weight daily.24 Once remission was observed, the dose was tapered to the lowest every-other-day dose. In another study, CyA was given orally at a dosage of 5 mg/kg body weight per day for 6 weeks.25 At the end of this trial, owners reported that pruritus decreased by 78%, and investigators reported a decrease in skin lesions by 58%.25 There was no difference in efficacy noted between prednisolone and CyA therapy. Cyclosporine administration was well tolerated in both of these studies, and both studies utilized the microemulsion formulation of CyA. Therefore, to treat most allergic patients, a suggested starting dose is 5 mg/kg body weight once daily, with further reduction of the dosage once symptoms have disappeared.dKetoconazole at 5 mg/kg body weight once a day can be added to the treatment protocol to decrease the dose and cost of CyA. If ketoconazole is combined, it is recommended that the starting dose of CyA be 2.5 mg/kg body weight once a day. It is best to avoid this combination therapy in patients with preexisting liver disease or in pregnant or nursing animals. Ketoconazole can also be beneficial in atopic cases with secondary Malassezia dermatitis. In cases of Malassezia dermatitis, the initial dose of ketoconazole is 5 to 10 mg/kg body weight once a day, and the CyA dose should be decreased to 2.5 mg/kg body weight once a day. These preliminary results show that the use of CyA alone or in combination with ketoconazole in the treatment of dogs with refractory atopic dermatitis is a safe and effective alternative to corticosteroid therapy.Cyclosporine has been effective in the management of perianal fistulas in dogs.82627 In one study, CyA was used as the sole agent to treat six cases at an initial oral dosage of 7.5 mg/kg body weight q 12 hours.27 After 1 week of therapy, whole blood CyA levels were measured, and the dose was adjusted to obtain a trough level of 400 to 600 ng/mL. Reduction in lesion size by 50% to 90% within 1 week of therapy was observed in all dogs. Resolution was noted in five of six dogs after 10 to 20 weeks of therapy.27 In another study, 85% of dogs had healed after 16 weeks of oral CyA at a dose of 5 mg/kg body weight q 12 hours.8 Surgical intervention tended to be less extensive than would have been required if the dogs had not been treated with CyA first, and the risk of postoperative complications (e.g., fecal incontinence, anal stricture) was therefore lower and postoperative management less extensive. Thus, CyA administration appears to be beneficial even in those dogs with fistulas that were not completely healed.82627The combination of ketoconazole and CyA can also lower the cost for treatment of perianal fistulas.20 In one study, 19 dogs with perianal fistulas were treated with a combination of ketaconazole (5.3 to 8.9 mg/kg body weight q 12 hours) and CyA (2 mg/kg body weight, 1 mg/kg body weight, 0.75 mg/kg body weight, or 0.5 mg/kg body weight q 12 hours). Serum trough levels of CyA were measured weekly and routine hematology and biochemistry biweekly. The target range for CyA was 400 to 600 ng/mL. Lesions resolved in 100% of dogs within 3 to 10 weeks. Cost was up to 80% less per day compared to CyA (5 mg/kg body weight q 12 hours) alone, and duration of treatment was also decreased. This study concluded that the use of ketaconazole (7.5 mg/kg body weight q 12 hours) and CyA (0.5 to 0.75 mg/kg body weight q 12 hours) was safe, effective, and economical for the treatment of perianal fistulas.20Cyclosporine was found to be ineffective in the treatment of epitheliotrophic lymphoma and various immune-mediated skin diseases.28 However, this was a small study and therapeutic drug monitoring was not performed, and treatment failure as a result of suboptimal CyA concentrations cannot be ruled out. A single case of a dog with granulomatous sebaceous adenitis that responded to CyA therapy has been reported.29Cyclosporine has been successful in the treatment of eosinophilic granuloma complex in cats. In a recent study, CyA (50 mg per cat per day) was most effective for oral collagenolytic granulomas and eosinophilic plaques, but not for indolent lip ulcers.30Renal transplants have been successfully maintained in cats by the use of CyA (7.5 mg/kg body weight q 12 hours) and prednisolone (0.125 to 0.25 mg/kg body weight q 12 hours). Cyclosporine dosages are adjusted to maintain whole blood trough concentrations of 500 ng/mL for 30 days after transplantation, and then they are reduced to maintain concentrations of 250 ng/mL thereafter.6 Cyclosporine has also been used successfully for bone-marrow transplantations in cats and experimentally for pancreatic islet, lung, and other transplantations.The purpose of this article was not to discuss every clinical usage of CyA that has been described, but to focus on the clinical indications where CyA has been proven beneficial in multiple cases. The use of CyA in refractory allergic dogs and cats gives veterinarians the option of a non-steroidal, safe, and effective alternative. The combination of CyA and ketoconazole can decrease the cost of CyA therapy; but, unfortunately, cost may still be a limiting factor in the clinical usage of CyA until a veterinary formulation is available.aOptimmune; Schering-Plough, Keniworth, NJbSandimmune; Sandoz, East Hanover, NJcNeoral; Novartis, Inc., East Hanover, NJdOlivry T, Bigler B, Fontaine J. Veterinary Dermatology list serve, 1999.