Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80–1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver. Graphical Abstract Similar content being viewed by others Data Availability AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our–science/clinical–trials/clinical–trials–data–and–information–sharing/data–and–information–sharing–with–qualified–researchers.htm.

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Medical writing support was provided by Stormy Koeniger, PhD, an AbbVie employee. Funding This work was funded by AbbVie. AbbVie contributed to the study design, research, interpretation of data, and the writing, review, and approval of this publication. Author information Authors and Affiliations Contributions DM, MJC, MS, and PM contributed to the conceptualization, methodology, and formal analysis of this work and writing of the manuscript. XS and TRJ contributed to the investigation, methodology, data analysis, and data curation for this work. All authors participated in the interpretation of data, final review, and approval of the manuscript. Corresponding author Ethics declarations Conflict of Interest All authors are current employees of AbbVie and may hold AbbVie stock or stock options. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Mukherjee, D., Chen, MJ., Shao, X. et al. Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling. AAPS J 25, 30 (2023). https://doi.org/10.1208/s12248-023-00794-6 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1208/s12248-023-00794-6