An area correction method to reduce intrasubject variability in bioequivalence studies.
OBJECTIVE
This paper investigates the use of a corrected area (AUC*K) to compensate for intrasubject variability in bioequivalence studies.


METHODS
Using computer simulation, this technique was applied to bioequivalence studies for two drugs. Both drugs exhibit first-order absorption and linear one-compartment disposition kinetics and total elimination by the liver. Drug I has a low intrinsic clearance (Cl(int)) and is not bound to blood components, while Drug II has a high Cl(int) and is highly bound. Two-way crossover trials, each including 24 subjects, were simulated using a spreadsheet program, which also performs ANOVA and provides 90% confidence intervals for C(max), AUC and AUC*K. The intrasubject CV for the parameter of interest was 30%. For all other pharmacokinetic parameters, the intrasubject CVs were 10%.


RESULTS
Drug I: With high variability in Cl(int), AUC's were concluded to be bioequivalent in 335, 303, 222, 102 and 32 of 500 trials for mean difference in % absorbed (DeltaA = [A(test) -A(ref)]x100/A(ref)), -5%, -10%, -15% and -20% respectively. The corresponding numbers of trials that passed for AUC*K were 500, 500, 500, 382 and 23. Drug II: With high variability in Cl(int), 273, 281, 190, 106 and 29 of 500 trials passed for AUC at DeltaA of 0%, -5%, -10%, -15% and -20% respectively. The corresponding numbers that passed for AUC*K were 378, 351, 239, 113 and 38 trials. For both drugs, when high variability was assigned to V, area correction reduced the number of trials passing for AUC. When the same intrasubject %CV was assigned to both Cl and V, area correction resulted in no change (Drug I) or a decrease (Drug II) in the number of passing trials. Assigning high intrasubject %CV to DeltaA did not appear to alter the outcome of the simulation.


CONCLUSIONS
Area correction appears to be helpful only when high intrasubject variability exists in clearance and not in the other parameters. It may be more helpful for drugs with low, compared to high Cl(int) since in the latter case variability in Cl(int) is reflected in both systemic clearance and bioavailability. It is recommended that area correction be attempted in bioequivalence studies of drugs where high intrasubject variability in clearance is known or suspected. It should be avoided where there appears to be a difference in K between treatments. The value of this approach in regulatory decision making remains to be determined.
Abdallah
H Y
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Division of Biopharmaceutics, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland, USA. hisham.abdallah@roche.com
D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency