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 F K506 in predicting doses to achieve target drug levels has been prospe ctively evaluated in transplant and autoimmune patients. For dose indi vidualization, the knowledge base is updated with patient-specific fee dback including the current dose, drug level, and the new target level . The study population of 147 patients consisted of 97 transplant pati ents (liver and kidney) and a 50 patients with autoimmune disorders. P atients in the transplant study group were entered sequentially and fo llowed as a cohort. Patients in the autoimmune study group were random ly assigned to one of three predefined FK506 concentration windows (lo w, -.1-.3; medium, 0.4-.7; and high, 0.8-1.3 ng/mL) as part of a conce ntration controlled clinical trial. Predictions of steady-state plasma drug levels were made throughout the clinical course of autoimmune pa tients and during the first 6 weeks post-transplant in liver and kidne y recipients. FK506 concentration in plasma was measured by a monoclon al antibody based ELISA assay. Accuracy was computed as the mean predi ction error (mpe). Precision was computed as the root mean squared pre diction 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 s tudy 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 popula tion nomograms and adaptive control feedback methods (least-squares an d Bayesian). Based on our findings, this IDS should have a number of i mportant uses relevant to the drug development process, the prescribin g physician and the individual patient. It provides an efficient metho d for implementing concentration controlled clinical trials. It should accelerate the physician's learning curve while at the same time help to maximize therapeutic drug efficient and minimize toxicity with dru gs exhibiting nonlinear kinetics and narrow therapeutic indices. Preli minary 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 ph armacoeconomic impact.