The role of metabolites in bioequivalency assessment. III. Highly variable drugs with linear kinetics and first-pass effect.
OBJECTIVE
Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CL(INT)) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%.


METHODS
Simulated PK studies were done using a linear first-pass model with CL(INT) 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 CL(INT) and its intrasubject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fraction metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75.


RESULTS
When CL(INT) values were raised above those for liver blood flow, the frequency of trials in which bioequivalence was correctly declared decreased when parent AUC was used as a bioequivalence criterion. Only when CL(INT) 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 assessment of bioequivalence. The Cmax for the metabolite was insensitive to changes related to rate of input, and when CL(INT) exceeded liver blood flow, evaluation of the metabolite Cmax data may lead to a conclusion of bioequivalence for products that were not.
Jackson
A J
AJ
Center for Drug Evaluation and Research, Division of Bioequivalence, Food and Drug Administration, Rockville, Maryland 20857, USA. Jacksonan@CDER.FDA.GOV
D000293:Adolescent; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D002997:Clomipramine / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007548:Isosorbide Dinitrate / Q000097:blood / Q000493:pharmacokinetics; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D016593:Terfenadine / Q000097:blood / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D003692:Delayed-Action Preparations; D006634:Histamine H1 Antagonists; D014665:Vasodilator Agents; D016593:Terfenadine; D007548:Isosorbide Dinitrate; D002997:Clomipramine