The role of partial area under the curve and maximum concentrations in assessing the bioequivalence of long-acting injectable formulation of exenatide_A sensitivity analysis.

To ensure therapeutic equivalence between the long-acting injectable (LAI) products, additional PK metrics other than C and AUC were considered necessary. However, regarding the selection of additional PK metrics for bioequivalence (BE) assessment of exenatide LAI, a discrepancy existed between EMA's and USFDA's product-specific guidance. The EMA recommends that both the maximum plasma concentration in the initial-release phase (C) and the extended-release phase (C) should be determined. Nevertheless, the USFDA recommends the use of the partial area under the curve (i.e., the area under the curve from week 4 to the last sampling point; pAUC). The focus of this study was to compare the sensitivity of different PK metrics, including C, C, pAUC, early and late pAUC metrics truncated at different time points (three, four, five, six and seven weeks), to formulation-related parameters and pharmacodynamic (PD) markers of glycemic control. A sensitivity analysis was conducted using the published PK/PD model of exenatide LAI. The results indicated that C and C exhibited comparable sensitivities. AUC was sensitive to changes in detecting the differences in formulation-related parameters and PD markers of glycemic control, but did not provide superior sensitivity performance compared to C and C. Among all tested PK metrics, AUC was found to be the most sensitive. The optimal cut-off time point for the pAUC should be set at the time of maximum plasma concentration in the extended-release phase (approximately 6-7 weeks). These results may provide useful insights into the selection of appropriate PK metrics for BE determination of exenatide LAI.