89626
document
Partial-area method in bioequivalence assessment : naproxen . Regulatory authorities require demonstration of bioequivalence through comparisons of different pharmacokinetic parameters , the area under the plasma concentration-time curve ( AUC ) , the maximum plasma concentration ( Cmax ) , and the time to reach peak concentration ( Tmax ) . The applicability and validity of regulatory requirements have been widely criticized on statistical and clinical relevance grounds . For most noncomplicated absorption models , the AUC correlates well with the extent of absorption . However , in nonlinear models of absorption , in mechanisms involving recycling of drugs , and for drugs with long half-life , the use of total AUC ( from zero to infinity ) can give erroneous and clinically irrelevant results since the area is mostly determined by elimination phase or by recycling . The calculation of total AUC also involves prolonged sampling , adding to the cost and risks associated with bioequivalence studies . The use of Cmax or Tmax as a measure of rate of absorption , to correlate with clinical relevance , is widely criticized on logical , technical , and statistical grounds . For drugs used on a multiple-dose basis , Cmax and Tmax evaluations become redundant since the average plateau concentration is not affected by these parameters . To resolve the drawbacks in the traditional methodology of bioequivalence evaluation , the use of partial areas in lieu of total AUC , Tmax , and Cmax is suggested . This study investigates the logic and robustness of the partial-area method in establishing bioequivalence . We conclude that the 5h AUC is a more relevant parameter to establish naproxen bioequivalence than AUCinf . We recommend against using symmetrical confidence intervals and report excellent agreement among several methods of calculating confidence intervals , probability values , and nonparametric tests . We suggest that a single-point short-term AUC is a better indicator of the bioequivalence of generic products than the total AUC , Cmax , and Tmax as required currently by the regulatory authorities .
89627
Intervention_Pharmacological
naproxen
89628
Intervention_Pharmacological
naproxen
89629
Outcome_Physical
area under the plasma concentration-time curve ( AUC ) , the maximum plasma concentration ( Cmax )
89630
Outcome_Physical
the time to reach peak concentration
89631
Outcome_Other
( Tmax )
89632
Outcome_Other
AUC
89633
Outcome_Other
AUC
89634
Outcome_Other
AUC
89635
Outcome_Other
Cmax
89636
Outcome_Other
Tmax
89637
Outcome_Other
Cmax
89638
Outcome_Other
Tmax
89639
Outcome_Physical
plateau concentration
89640
Outcome_Other
AUC
89641
Outcome_Other
Tmax
89642
Outcome_Other
Cmax
89643
Outcome_Other
5h AUC
89644
Outcome_Other
AUCinf
89645
Outcome_Other
single-point short-term AUC
89646
Outcome_Other
AUC
89647
Outcome_Other
Cmax
89648
Outcome_Other
Tmax
89649
Participant_Condition
Partial-area method in bioequivalence
89650
Participant_Condition
bioequivalence