COMPUTER-GUIDED RANDOMIZED CONCENTRATION-CONTROLLED TRIALS OF TACROLIMUS IN AUTOIMMUNITY - MULTIPLE-SCLEROSIS AND PRIMARY BILIARY-CIRRHOSIS

A randomized concentration-controlled clinical trial (RCCCT) is a tria l design in which patients are randomized to predefined blood drug con centrations (low, medium, high). If the concentration ranges are suffi ciently separated, this study design can reveal important blood concen tration-response relations. Tacrolimus is a potent yet ''infant'' immu nosuppressant for the treatment and prevention of graft rejection and has been shown to exhibit significant clinical activity in some immune -mediated disorders. A tacrolimus artificial intelligence modeling sys tem (AIMS) was used to guide patient dosing to achieve target concentr ations specified by the study protocols. In the Multiple Sclerosis stu dy group, we were able to define a concentration range (0.3-0.7 ng/ml) that appeared to show efficacy and minimal tacrolimus toxicity. Patie nts randomized to the high zone (0.6-1.2 ng/ml) in the Primary Biliary Cirrhosis study group showed significant reduction (similar to 50%) i n surrogate efficacy markers [aspartate aminotransferase (SGOT), alani ne aminotransferase (SGPT)] compared with patients in the low zone (0. 1-0.6 ng/ml). Therefore the RCCCT allowed the detection and delineatio n of clinically significant concentration-response relations in an eth ical and efficient manner.