The use of therapeutic drug monitoring to optimise immunosuppressive therapy.
Most experience of the therapeutic drug monitoring of immunosuppressive agents has been acquired in the field of solid organ transplantation; however, agents such as cyclosporin (cyclosporin A) are being increasingly utilised for the management of autoimmune diseases. Cyclosporin is the most widely studied immunosuppressant, but in spite of this many controversies still exist as to the optimum strategy for monitoring this drug. Owing to its widely variable pharmacokinetics and metabolism, and the absence of a simple method to measure therapeutic effectiveness, many factors should be considered. In most circumstances, measuring whole blood through concentrations of cyclosporin with a specific assay methodology is warranted. In addition, knowledge of other factors that may alter the pharmacokinetics (such as liver function, concomitant food or medications, gastrointestinal status, and time since transplantation) should be taken into account so that therapy can be appropriately adjusted. Other methods of monitoring have been investigated, such as AUC (area under the concentration-time curve) monitoring and immunological monitoring. However, further refinement of these techniques and greater experience with their efficacy must be accumulated before their role in the monitoring of cyclosporin can be defined. Tacrolimus, like cyclosporin, shares many of the difficulties in monitoring for efficacy and toxicity due largely to the variable pharmacokinetics; similarly to cyclosporin, whole blood through concentration monitoring should be utilised in combination with knowledge of the factors that may affect the pharmacokinetics. Muromonab CD3 (OKT3) is a monoclonal antibody used for the treatment and prophylaxis of acute allograft rejection. Several immunological monitoring techniques have been investigated for this agent. Monitoring CD3+ levels can assist clinicians in determining therapeutic efficacy, while measuring antimuromonab CD3 antibody titres can help determine if xenosensitisation has occurred, causing therapeutic ineffectiveness. The clinical monitoring of azathioprine, one of the first immunosuppressive agents used in transplantation, has historically been limited to monitoring complete blood counts for bone marrow suppression. However, newer techniques measuring intracellular DNA nucleotides appear to be promising. The new immunosuppressants on the horizon include mycophenolate mofetil and rapamycin. The clinical experience with therapeutic drug monitoring of these 2 compounds is scant in the literature; however, both agents have demonstrated efficacy in preventing or treating allograft rejection while maintaining a relatively well tolerated toxicity profile in recent clinical trials. Routine monitoring does not appear to be warranted for immunosuppressive therapy in autoimmune diseases.
Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts, USA.
S M
SM
Tsunoda
F T
FT
Aweeka
D001327:Autoimmune Diseases / Q000188:drug therapy; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D015507:Drugs, Investigational; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015166:Monitoring, Immunologic; D011863:Radioimmunoassay; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
D017252:CD3 Complex; D015507:Drugs, Investigational; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001379:Azathioprine; D016559:Tacrolimus