An intelligent and cost-effective computer dosing system for individualizing FK506 therapy in transplantation and autoimmune disorders

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Figure 1

Scattergrams of predicted versus observed FK506 levels are shown for each study group in the combined group. These graphs show the close correlation between the observed and predicted FK506 plasma levels in each study group. The study groups are as follows: a. Kidney, liver, and autoimmune disease patients; b. Kidney transplant recipients; c. Liver transplant recipients; d. Patients with autoimmune diseases.

Figure 2

Scattergram of the observed relationship between FK506 dose over a wide range (0.5–60 mg/day) and the corresponding FK506 plasma level at steady-state in the combined study population. The marked intersubject variability and the lack of a simple linear relationship (r² = .0034) between FK506 dose and achieved steady-state plasma level is evident.

Figure 3

A three-dimensional surface plot of the relationship between current dose, new dose and the percent change in FK506 level is depicted. The surface area of the nonlinear plane observed was calculated using Design CAD 3D, a software package which uses surface integrals to make the surface area calculation.

Figure 4

A three-dimensional plot of the modeled relationship between the three variables (current dose, new dose and percent change in FK506 level) is shown. The disproportionate increase in the surface area between nonlinear plane and a linear plane with increasing doses of FK506 can be readily seen.