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An Intelligent and Cost‐Effective Computer Dosing System for Individualizing FK506 Therapy in Transplantation and Autoimmune Disorders

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient‐specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1–.3; medium, 0.4–.7; and high, 0.8–1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady‐state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post‐transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), −0.034 ng/mL (kidney), and −0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients. The performance of the FK506 compares favorably with previously reported pharmacokinetic dosing methods such as population nomograms and adaptive control feedback methods (least‐squares and Bayesian). Based on our findings, this IDS should have a number of important uses relevant to the drug development process, the prescribing physician and the individual patient. It provides an evident method for implementing concentration controlled clinical trials. It should accelerate the physician's learning curve while at the same time help to maximize therapeutic drug efficacy and minimize toxicity with drugs exhibiting nonlinear kinetics and narrow therapeutic indices. Preliminary studies suggest that these assets result in a significant cost‐benefit advantage by reducing the duration of hospitalization. Current studies are in progress to validate this and carefully measure its pharmacoeconomic impact.