Immunosuppressive and Immunomodulatory Drugs at a Glance
- The main goals in immunotherapy are safety and effectiveness.
- Unlike immunomodulators, immunosuppressive drugs are all characterized by a narrow therapeutic window requiring precise dosing and close side-effect monitoring.
- The highest level of safety and effectiveness in immunotherapy therapy is currently accomplished by the use of combined regimens.
- An additive or synergistic combined immunotherapeutic regimen allows significant reduction of dose-dependent drug side effects maintaining or improving the effectiveness, respectively.
- A comprehensive knowledge of the pathophysiology of the treating disease as well as of the pharmacokinetics and pharmacodynamics concepts is crucial for delineating the most effective and safest therapeutic regimens.
There has been significant progress in the search for selective immunomodulation; the most significant advance in immunotherapy has been the reduction of systemic corticosteroid therapy by the early or concomitant introduction of immunosuppressive therapies. Immunosuppressants are characterized by (1) a low therapeutic index (narrow window between the therapeutic and toxic range) and (2) intra- and interindividual variation of the pharmacokinetics of these agents. These obstacles are usually overcome by precise drug dosing (ideal/lean body weight) as well as close monitoring of drug levels (parent and metabolite serum peak and trough levels) and end-organ toxicity. The main goals in immunotherapy are safety and effectiveness, which currently are accomplished by the use of combination therapy.1,2 (See Fig. 233-1.) Although in transplantation medicine, agents are often combined, in dermatologic usage, these agents are usually used as corticosteroid-sparing agents and are less frequently used in combination except perhaps with methotrexate.3 Within the dermatologic community, the use of cyclosporine and related macrolactam drugs has fallen with the introduction of biologic agents targeted more precisely at the presumed pathogenetic factors. In addition, many of the biologic agents have less toxicity than these broad-spectrum immunosuppressive therapies. However, the use of mycophenolate mofetil has increased within the dermatologic community.
A modified, median-effect formula is widely used in organ transplant, which helps in finding the therapeutic windows of immunosuppressive drugs as well as the synergistic, additive, or antagonistic effect of a postulated drug combination. Igs = immunoglobulins. (From Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27, 1984.)
Mycophenolate mofetil (MMF) is an ethyl ester of its active metabolite, mycophenolic acid (MPA)—a product of several Penicillium species.
MMF is the reformulated product of MPA, but with enhanced bioavailability. MPA inhibits the type II isoform of inosine monophosphate dehydrogenase in the de novo pathway of purine synthesis. The proliferation of both T- and B-lymphocytes are susceptible to this drug effect, because they minimally use the hypoxanthine–guanine phosphoribosyl transferase salvage pathway for purine synthesis. Decreased delayed hypersensitivity and immunoglobulin levels have been observed in treated patients.