EXISTING AND NEW CRITERIA FOR BIOEQUIVALENCE EVALUATION OF NEW CONTROLLED-RELEASE (CR) PRODUCTS OF CARBAMAZEPINE

While the three classical pharmacokinetic (PK) parameters, AUG, C-max and t(max) are adequate to assess bioequivalence of immediate release (CR) formulations, they are not designed to fully characterize the pha rmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (C BZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (par ameters). The following are the proposed new parameters: MRT (mean res idence time), C-max/AUC, plateau time or POT (the time span associated with the concentrations within 25% of C-max) tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mea n of the concentrations within 25% of C-max). The above proposed param eters, were utilized in a recent PK study of new CR products of CBZ (6 00 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ C R formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reach ed utilizing both the classical and the proposed new parameters. The n ew parameters showed that CBZ 600 granulate has similar rate of absorp tion as the two 600 mg CR tablets, but its extent of absorption was lo wer. The new parameters examined in this paper are more attractive tha n the single point parameters, C-max and t(max), for assessment of rat e of absorption and the flatness of the plasma concentration versus ti me curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is import ant in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ pl asma concentration curve on the drug efficacy and tolerability. (C) 19 98 Elsevier science B.V. All rights reserved.