COMPUTER-GUIDED CONCENTRATION-CONTROLLED TRIALS IN AUTOIMMUNE DISORDERS

A randomized concentration-controlled clinical trial (RCCCT) is an alt ernate experimental design to the standard dose-controlled study. In a RCCCT, patients are randomly assigned to predefined plasma or blood d rug concentration ranges (low, medium, and high). With the caveat that concentration ranges are sufficiently separated, this design should e nhance the ability to discover important concentration response relati onships. FK-506, a potent and promising immunosuppressive agent for pr evention and treatment of graft rejection, has shown significant clini cal activity in some immune-mediated disorders. To implement the RCCCT design, a novel FK-506 intelligent dosing system (IDS) was used to gu ide all doses to prospectively achieve the target concentration range specified in the study protocol. Patients enrolled in these trials suf fered from a variety of autoimmune disorders, including multiple scler osis, primary biliary cirrhosis, psoriasis, autoimmune chronic active hepatitis, and nephrotic syndrome. We observed excellent predictive pe rformance of the IDS for all patients. The accuracy (mean prediction e rror) of the IDS was -0.022 ng/ml and the precision (standard deviatio n of the prediction error) was 0.119 ng/ml. Thus, the IDS is both accu rate and reproducible for autoimmune patients. We conclude that the RC CCT design, guided by an accurate and precise IDS, is an informative a nd cost-effective approach for evaluation of efficacy and safety of ef fective but highly toxic agents.