Evaluation of a Cmin and a normalized Cmin method for the confirmation of steady-state in bioequivalence studies.
OBJECTIVE
Two methods to confirm attainment of steady-state conditions in multiple-dose bioequivalence studies are described and evaluated: (1) the Cmin method and (2) the Area Below the Cmin plasma-concentration-versus-time-curve method (ABCM method).


METHODS
Cmin Method-After repetitive drug administration to presumed steady-state, successive trough, or Cmin, values are evaluated to determine if they are equal. ABCM Method-The ABCM of successive doses from dose two to presumed steady-state [ABCM(ss)] are divided by the ABCM for the first dose, ABCM(t), to give ABCM(ss)/ ABCM(t)=R, which describes the increase in ABCM(n) with successive doses. The quantity, R, is then divided by an accumulation ratio to render the value independent of intra-subject clearance differences. Monte Carlo simulations were done to test the effects of data error and slow-clearing subpopulations on the method's performance. Data from multiple-dose bioequivalence studies were evaluated using confidence intervals for both methods to determine how well each predicted steady-state for immediate-release and controlled-release drug products.


CONCLUSIONS
The Cmin method more accurately predicted the attainment of steady-state conditions for immediate-release formulations compared to the ABCM method. Conversely, the ABCM procedure more accurately predicted the attainment of steady-state conditions for controlled-release formulations compared to the Cmin method. The simulation results were further supported by the experimental data.
Center for Drug Evaluation and Research, Division of Bioequivalence, Food and Drug Administration, Rockville, Maryland 20857, USA.
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Jackson
D000293:Adolescent; D000328:Adult; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics; D001825:Body Fluid Compartments; D002744:Chlorpheniramine / Q000008:administration & dosage / Q000493:pharmacokinetics; D003198:Computer Simulation; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D006801:Humans; D008297:Male; D008432:Mathematical Computing; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
D018926:Anti-Allergic Agents; D000962:Antimalarials; D003692:Delayed-Action Preparations; D002744:Chlorpheniramine; D011802:Quinidine