A method is presented for prediction of the systemic drug concentration profile from in vitro release/dissolution data for a drug formulation. The method is demonstrated using four different tablet formulations containing 200 mg carbamazepine (CZM), each administered in a four way cross-over manner to 20 human subjects, with 15 blood samples drawn to determine the resulting concentration profile. Amount versus time dissolution data were obtained by a 75 rpm paddle method for each formulation. Differentiation, with respect to time, of a monotonic quadratic spline fitted to the dissolution data provided the dissolution rate curve. The dissolution curve was through time and magnitude scaling mapped into a drug concentration curve via a convolution by a single exponential, and the estimated unit impulse response function. The method was tested by cross-validation, where the in vivo concentration profiles for each formulation were predicted based on correlation parameters determined from in vivo-in vitro data from the remaining three formulations. The mean prediction error (MPE), defined as the mean value of 100% x(observed-predicted)/observed was calculated for all 240 cross-validation predictions. The mean values of MPE were in the range of 10-36% (average 22%) with standard deviations (S.D.s) in the range of 9-33% (average 13%), indicating a good prediction performance of the proposed in vivo-in vitro correlation (IVIVC) method.
Copyright 2000 John Wiley & Sons, Ltd.