Evaluation of truncated AUC as an alternative metric to assess pharmacokinetic comparability in biologics development
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background
Assessment of pharmacokinetic (PK) comparability involves measuring the area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax). For biologics products, the current practice has been sampling for an adequate duration (3-5 half-lives) to capture the full PK profile which may translate into long study duration of months for certain products. For small molecule drugs with long half-lives, truncated AUC, i.e., AUC from time 0 to a certain pre-determined time point, is used in assessing the AUC metric in the determination of bioequivalence in generic drug product development arena. Objectives: The goals of this project are to 1) evaluate if truncated AUC can be used especially in the case of subcutaneously (SC) administered biologics which have multiple of presentation such as autoinjectors (AI) or pre-filled syringes (PFS), etc. and 2) identify appropriate duration for assessment of truncated AUC to assess PK comparability. Truncated AUC will be evaluated based on: 1. Consistency with total AUC (AUC0-t, AUC0-∞), which are the current standard parameters measured for understanding systemic exposure and comparability. 2. Appropriate time cut-off for truncated AUC which is critical to ensure completion of the absorption phase of the therapeutic proteins under study. 3. Comparison of variability (calculated by coefficient of variation, CV) for truncated AUC vs total AUC
Methods
A comprehensive search of the “Drugs@FDA” database was conducted to indentify FDA-approved biologics as of July 6, 2021Biologics License Applications (BLAs) that have both PFS and AI presentations for SC administration were selected, which included reference products and corresponding biosimilars. The 90% confidence intervals (CI) of geometric mean ratio of AUC0-t, AUC0-∞, AUC0-7 (AUC from time 0 to day 7), AUC0-14 (AUC from time 0 to Day 14), and AUC0 -21 (AUC from time 0 to Day 21) for the selected products were calculated to determine if the ratios were within the range of 80-125%. The geometric means and CV were calculated for each scenario to see if there is a statistically significant difference in the variability in the different PK metrics. All the calculations and statistical analyses were performed using R software (version4.1.0) and RStudio(version 1.4.1717).
Results
Based on the completed datasets analyzed for 11 BLAs, there was a good agreement in the comparability assessment based on truncated AUC up to 14 days and 21 days and total AUC. The incidence of anti-drug antibody was generally lower at the time when truncated AUC is assessed as compared to that at the end of the study when total AUC is evaluated. Based on the estimation of the geometric CV, the variability for truncated AUC was lower or comparable to total AUC.
Conclusion
Based on the preliminary data analysis of datasets analyzed thus far, utilization of truncated AUC for therapeutic biologics with a long half-life appears to be sensitive and adequate to determine if the two presentations (e.g., AI and PFS) provide comparable systemic bioavailability. The appropriate time frame for assessment of truncated AUC could be ascertained from the available PK profile. Using truncated AUC as a metric for PK comparability has shown promise and a confirmation of this approach will be immensely beneficial as it can reduce the number of site visits required and reduce study time and costs. Other factors such as potential impact of immunogenicity on the findings will be evaluated. However, these results need to be further confirmed by analyzing a large number of datasets and further research in this area is ongoing.
References
1. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (fda.gov)