immunosuppressant. It was approved by the FDAin 1994 for use in liver transplantation. The drug use in uveitis has been described since 1991.

Pharmacology

Absorption of tacrolimus from the gastrointestinal tract is both incomplete and variable. The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is primarily metabolized by the cytochrome P-450 system. Fecal elimination accounts for over 90% of elimination. The average half-life of tacrolimus is about 35 hours. Tacrolimus crosses the placenta and is excreted in human milk.1

Drug effects in human nonocular diseases

Tacrolimus is FDA-approved to prevent and treat liver, kidney, or heart transplant rejection. It is also used in the treatment of ulcerative colitis and atopic dermatitis.

Drug use in retinal diseases

Sloper et al.9 demonstrated that tacrolimus has a useful role as an immunosuppressive agent for the treatment of sight-threatening uveitis (3 patients had Behçet’s disease, 1 had microscopic polyangiitis, 1 had pars planitis, and 1 had idiopathic retinal vasculitis) in patients who did not respond to CsA either because of lack of therapeutic effect or unacceptable adverse effects. The posterior uveitis remained controlled in all 6 patients while they were taking tacrolimus. Five of the 6 patients showed improvement, defined as improvement of 2 lines or more of Snellen acuity or a decrease in the binocular indirect ophthalmoscopy score.

Hogan et al.10 showed in a retrospective case series of 62 consecutive patients with noninfectious uveitis that tacrolimus’s efficacy is maintained long-term, and its cardiovascular risk profile is excellent. The patients successfully tapered their oral prednisone to 10 mg daily, with an 85% probability of achieving ≤ 10 mg after 1.2 years of treatment. There was no requirement for alternative second-line immunosuppressive therapy and the rate of tacrolimus dose reduction or discontinuation due to side-effects was minimal.

Drug mechanism, systemic and ocular complications and toxicity, drug interactions and contraindications are summarized in Table 36.1.2,6–8

Summary and key points

CsA and tacrolimus are effective second-line agents. However, despite the use of low-dose regimens, CsA toxicity (renal toxicity, hypertension) remains an important problem. This forms a major limitation to successful long-term treatment with CsA.

Tacrolimus may cause fewer adverse effects when compared with CsA in part due to its greater immunosuppressive potency and therefore lower dose, but it is used less frequently.

ANTIMETABOLITES

MYCOPHENOLATE MOFETIL (MMF)

Key features, introduction, and history

MMF is a prodrug derived from the fungus Penicillium stoloniferum. The drug use in uveitis has been described since 1998.

Pharmacology

MMF has high oral bioavailability and is absorbed within 30 minutes. It is metabolized in the liver to the active compound mycophenolic acid, which is excreted renally.6

Drug mechanism

MMF is a selective inhibitor of inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophos-

phate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. It prevents lymphocyte proliferation, suppresses antibody synthesis, interferes with cellular adhesion to vascular endothelium, and decreases recruitment of leukocytes to sites of inflammation.6

Drug effects in human nonocular diseases

MMF is FDA-approved for prevention of renal, cardiac, or hepatic allograft rejection and is also used in systemic lupus erythematosus, Crohn’s disease, nephrotic syndrome, and psoriasis.

Drug use in retinal diseases

Thorne et al.11 evaluated MMF treatment outcomes in 84 patients with inflammatory eye disease. After 1 month of treatment, 96.4% of patients had control of their ocular inflammation. Treatment success, as judged by the ability to control the inflammation and taper the prednisone to <10 mg daily, was achieved in 60 patients (71%). The median time to treatment success after the institution of MMF was 3.5 months. Approximately 18% of patients required the addition of a second immunosuppressive drug, and, of these patients, 71% had control of their disease. MMF starting dose was 2 g. However, 11% of patients required an increase in the dose of MMF to 3 g daily.

Siepmann et al.12 evaluated the outcomes of 106 patients with different forms of chronic uveitis treated with MMF at a dose of 1 g twice daily. The number of recurrences was 0 or 1 in 92 patients, 2 in 6 cases and 3 or more in 8 patients. In none of the patients had MMF been stopped at the time of data analysis.

Sobrin et al.13 evaluated the outcomes of treatment with MMF in 85 patients with scleritis and uveitis refractory to or intolerant of methotrexate. They demonstrated that MMF was effective in controlling inflammation in approximately half of the patients who had previously failed with or did not tolerate methotrexate.

Pediatric case series

Doycheva et al.14 assessed the efficacy of MMF in 17 children (32 eyes) with chronic noninfectious uveitis who received MMF for at least 6 months. The average maintenance dose was 1 g daily (range 750 mg to 2 g daily). A steroid-sparing effect was achieved in 88% of patients. Twenty-four percent of patients remained relapse-free during the treatment, but a reduction in the relapse rate was observed in all other patients except one. Visual acuity was increased or maintained in 13 children (76%).

Drug mechanism, systemic and ocular complications and toxi­ city, drug interactions, and contraindications are summarized in Table 36.2.2,6–8

METHOTREXATE

Key features, introduction, and history

Methotrexate is a folic acid analogue that was originated in the 1940s when folic acid effects were tested on children with acute leukemia. It gained FDA approval as an oncology drug in 1953. The drug use in uveitis has been described since 1966.

Pharmacology

Methotrexate is metabolized by intestinal bacteria and the percentage of oral absorption decreases as the dose increases. It is eliminated primarily through the kidney. The half-life is approximately 3–10 hours.2,6

Drug mechanism

Methotrexate is a folic acid analogue and an inhibitor of dihydrofolate reductase, the enzyme responsible for the conversion of dihydrofolate to tetrahydrofolate. This action inhibits the production of thymidylate, which is essential for DNA replication. It inhibits rapidly dividing cells, such as leukocytes, producing an anti-inflammatory effect.2,6

Diseases Retinal in Mechanisms and Drugs • 4 section