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.
Jackson
A J
AJ
Center for Drug Evaluation and Research, Division of Bioequivalence, Food and Drug Administration, Rockville, Maryland 20857, USA.
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