The role of metabolites in bioequivalency assessment. III. Highly variabledrugs with linear kinetics and first-pass effect

Purpose. Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CLINT) on the probability of meeting bioequi valence criteria for extent (AUC) and rate (Cmax) of drug absorption when t he absorption rate and fraction absorbed (F) were formulated either to be e quivalent or to differ by 25%. Methods. Simulated PK studies were done using a linear first-pass model wit h CLINT values ranging from 15 L/HR to 900 L/HR. Test/ Reference absorption rate constants (Ka) and fraction absorbed (Fa) ratios of 1.0 or 1.25 were used for all simulations. The impact of the value of CLINT and its intrasub ject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fractio n metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75. Results. When CLINT values were raised above those for liver blood flow, th e frequency of trials in which bioequivalence was correctly declared decrea sed when parent AUC was used as a bioequivalence criterion. Only when CLINT exceeded liver blood flow did the metabolite become important in assessing extent of absorption. Conclusions. The Cmax for the parent drug provided the most accurate assess ment of bioequivalence. The Cmax for the metabolite was insensitive to chan ges related to rate of input, and when CLINT exceeded liver blood flow, eva luation of the metabolite Cmax data may lead to a conclusion of bioequivale nce for products that were not.