Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half‐Life

Abstract

Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC 0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CV w ) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC 0-72 in relation to AUC 0-48 and AUC 0-24 , according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CV w of AUC truncated at 72, 48 and 24 hr was compared with the CV w of AUC 0-12 . There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC 0-72 , Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CV w was worse for AUC 0-12 than AUC 0-24 or AUC 0-48 . These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.The European guidelines for conducting bioequivalence studies of immediate-release formulations state that two formulations are bioequivalent if the 90% confidence interval (CI) of the ratio of the means for the pharmacokinetic parameters (area under the plasma concentration curve from administration to the last observed concentration at time t [AUC 0-t ] and maximum plasma concentration [C max ]) of the test and reference formulations is within the acceptance interval of 80.00-125.00% [1,2]. In the case of drugs with a long half-life, the latest update of these guidelines proposes truncating the AUC at 72 hr (AUC 0-72 ) as an alternative to calculating the AUC 0-t for comparison of the extent of exposure, as the absorption phase is completed during the first 72 hr [1]. Furthermore, the absorption phase of a drug in its plasma concentration versus time is more sensitive and decisive and enables better detection of the differences between formulations before the drug is completely eliminated [3]. Therefore, a sampling period longer than 72 hr is not necessary for immediate-release formulations, irrespective of half-life [1].Complete absorption of the drug formulation occurs mostly within the first 24 hr; therefore, truncation of the AUC at 24 or 48 hr as the primary parameter should be enough. Moreover, as absorption is the most relevant parameter in shorter AUCs, these intervals could be more sensitive for calculating differences between formulations.An AUC t...

Evaluation of Truncated AUC as an Alternative Measure to Assess Pharmacokinetic Comparability in Bridging Biologic–Device Using Prefilled Syringes and Autoinjectors

“…For small molecules with a long elimination half‐life, it is well‐accepted to use tAUC in lieu of AUC 0–inf , given that the tAUC can cover the complete absorption phase 7 . The utility of tAUC has also been demonstrated in several clinical and modeling and simulation studies of small‐molecule drugs 45–51 . Our study demonstrated that to bridge the PFS and AI , tAUC evaluated until day 28 post‐dose can achieve high concordance (≥85%) for biologics that exhibit linear or nonlinear elimination with k a values greater than or equal to 0.1/day and with a typical sample size of 70 subjects per arm.…”

“…7 The utility of tAUC has also been demonstrated in several clinical and modeling and simulation studies of smallmolecule drugs. [45][46][47][48][49][50][51] Our study demonstrated that to bridge the PFS and AI , tAUC evaluated until day 28 post-dose can achieve high concordance (≥85%) for biologics that exhibit linear or nonlinear elimination with k a values greater than or equal to 0.1/day and with a typical sample size of 70 subjects per arm. tAUC 0-28 could be used appropriately to evaluate PK comparability between the two presentations, even for biologics with a long elimination half-life of 40 days, to reduce the study duration compared with an evaluation of AUC 0-inf .…”