Cyclosporine is a potent immunomodulator that has been in widespread use for nearly 3 decades. Systemic dosing of 2 to 10 mg/kg per day is administered orally or intravenously for immunosuppression after organ transplantations (kidney, heart, liver, and lung allografts) and treatment of various immunologic and autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, and moderate to severe psoriasis.18–21
Ocular diseases that have been treated with systemic cyclosporine include uveitis, Behçet’s disease, and bird shot retinochoroiditis as well as prophylaxis and treatment for rejection of corneal and limbal stem cell allografts.22–25
Cyclosporine is a neutral, hydrophobic, cyclic undecapeptide with a molecular weight of 1.2 kDa. Given its physicochemical properties and hydrophobicity, cyclosporine has presented ocular formulation challenges that provide adequate concentration, stability, reliable drug delivery, and acceptable vehicle safety.26
To improve delivery of cyclosporine to ocular tissues, a castor oil–water emulsion formulation was developed and used for topical cyclosporine 0.05% (Restasis; Allergan) that produces sustained cyclosporine concentrations sufficient for immunomodulation in external ocular tissues. On instillation directly into the eyes, cyclosporine partitions from the oil droplets into ocular surface tissues. The ocular retention time for this emulsion vehicle has been estimated as approximately 2 hours.27
Ocular absorption and tissue distribution of cyclosporine after topical administration have been studied extensively in rabbits and dogs.27–32
Bioavailability of topical cyclosporine ophthalmic solutions can be improved either by raising the drug concentration or by higher-frequency administration. It has been shown that cyclosporine concentrations in the conjunctiva, cornea, and lacrimal gland increase as the cyclosporine strength in the castor oil–water emulsion increases from 0.05% to 0.2%.33
Work by Acheampong et al27
has also shown that after repeated administration of the castor oil–water emulsion formulation, cyclosporine accumulation increases in the conjunctiva, cornea, and lacrimal gland. In systemic immunosuppressive therapy for organ transplants, cyclosporine has shown clear dose–response effects.34,35
Using a mouse heart transplant model, a close relationship has been shown between cyclosporine dose and its immunosuppressive potency.14
These data are also consistent with observations in patients who have been treated with cyclosporine.34,36
The dose–response nature of systemic cyclosporine allows clinicians to adjust and individualize the cyclosporine dosing in different phases of immunosuppression based on the clinical status of the patient.
Notwithstanding what we report here, both phase II and III clinical trials of topical cyclosporine failed to demonstrate clear dose–response relationships among the different cyclosporine concentrations.1,2
Although the higher concentrations of cyclosporine were demonstrated to be safe, the lack of any additional therapeutic benefit with increasing the concentration led to approval of the cyclosporine 0.05% formulation for twice-daily dosing. In our series, however, the majority of patients with severe dry eye disease who had inadequate responses (limited improvement but still with significant residual symptoms and/or signs of dry eye disease) to twice-daily use of cyclosporine 0.05% showed significant improvement to more frequent (3–4 times a day) dosing. The apparent additive effect of more frequent use of topical cyclosporine 0.05% in an objective measure (corneal staining) () strongly suggests that the subjective improvements are a result of an improvement in the underlying immunopathology of the disease and not just symptomatic changes. The significant decrease in corneal staining is of particular relevance because it represents an improvement in the health of the ocular surface caused by the additional suppression of inflammatory processes. There have been reported cases of severe dry eye disease that failed conventional therapy, including topical cyclosporine 0.05%, but that eventually responded to systemic immunosuppressive therapy, including systemic cyclosporine.37
Taken together, these findings suggest that a group of patients with severe inflammatory dry eye disease may need further immunosuppression than that afforded by twice-daily application of topical cyclosporine 0.05%.
Because cyclosporine 0.05% is the only commercially available ophthalmic emulsion, and the custom-made higher concentrated topical preparations are not readily available, therefore, the most convenient solution for augmenting the bioavailability of topical cyclosporine is to increase the frequency of its application. Given that the ocular retention time for cyclosporine emulsion is approximately 2 hours, potential effectiveness of a higher-frequency regimen is certainly conceivable. Higher-frequency topical cyclosporine would increase the residency time of medication. This could potentiate greater absorption of medication and increase the probability of a greater therapeutic response.
In our study, none of our patients showed any drug-related adverse events not seen with the lower-frequency application of twice a day. This observation is consistent with previous extensive preclinical and clinical safety studies of topical cyclosporine.1,2,38,39
In a preclinical safety study, Angelov et al39
have shown no ocular or systemic toxicity with long-term ocular administration of cyclosporine at concentrations up to 0.4% given as many as 6 times daily for 6 months in rabbits and 1 year in dogs. Serum cyclosporine concentration after twice-daily ocular administration of cyclosporine 0.05% and 0.1% has also been shown to be extremely low or undetectable in rabbits, dogs, and humans, obviating concerns about systemic toxicity.38,39
The present study has certain limitations. Small sample size, heterogeneity of the patient population/treatment regimen, and the absence of a comparison or control group are the major drawbacks of this study. The improvement observed in our study population may not only be the result of a direct effect of higher dose–response of cyclosporine itself, but also other properties of the formulation other than cyclosporine content (eg, the vehicle). In phase II and III clinical trials, the vehicle used in the cyclosporine ophthalmic emulsion provided substantial palliative benefits, producing significant improvements in several outcome measures, particularly in the early follow-up period.1,2
This prominent vehicle effect prompted subsequent marketing of the vehicle as a tear-stabilizing lubricant with prolongation of tear breakup time.40
The significant improvement in the objective sign (corneal staining) of disease in our study patients, however, suggests that the treatment effect is likely not purely palliative in nature and represents the added therapeutic effect of higher-frequency dosing of topical cyclosporine 0.05%. To further address this issue, well-controlled (including vehicle control) studies using different frequencies of topical cyclosporine are clearly required.
In summary, our findings suggest that patients with severe inflammatory forms of dry eye disease such as ocular GVHD or SS may benefit from more frequent dosing of topical cyclosporine 0.05% than twice daily.