EFFECT OF DIFFERENT MATHEMATICAL-METHODS ON ETOPOSIDE AREA-UNDER-THE-CURVE ESTIMATIONS AND PHARMACODYNAMIC - RESPONSE PREDICTIONS

Different methods to calculate interval area under the curve (AUC) dat a may produce substantial error. The purpose of this study was to comp are methods of calculating etoposide AUC and determine the effect of t hese values on white blood cell (WBC) count nadir predictions calculat ed from a previously reported equation. Three AUC calculation methods were used: (1) the linear trapezoidal method, (2) a combination of the linear and logarithmic trapezoidal methods, and (3) the Lagrange meth od. Since none of the methods for determining the AUC could be conside red the standard, the methods were evaluated by comparing differences between pairs of calculated AUC values by each method, The 95% CI for differences between all pairs of AUC values were greater than zero (no difference) indicating significance. Consistent with the smoother fit ting function between data points, the Lagrange method tended to produ ce a larger AUG, lower clearance values, arid lower WBC nadir count pr edictions than the other methods. The largest difference encountered w as between the Lagrange and the linear-log AUC methods with a mean val ue of 16.9 mu g h/ml (95% CI 9.4-24.3) This difference would al:count for approximately 11% of the total AUC. Using a previously published e quation, where WBC nadir = -0.057 + 0.048 x etoposide clearance, with clearance determined as dose/AUC, mean differences in calculated WBC n adir count values between the three AUC methods ranged from 80 to 220 cells/mu l, which would be expected to be of little clinical consequen ce. The precision of this equation, using data derived from linear tra pezoidal AUC calculations, had a mean absolute error of 0.93 x 10(3)/m u l (95% CI 0.53-1.32). Our findings suggest that any of the three mat hematical methods studied would produce similar etoposide AUC values a nd pharmacodynamic pre dictions. Further, these findings also suggest that the major limitation in predicting etoposide leukopenia lies with the imprecision of the pharmacodynamic model more so than the ability to accurately determine the AUG. However, our findings may not be app licable if other factors intervene which dramatically alter the shape of the etoposide concentration-time curve.