Clinical Pharmacology, AbbVie, Inc., Building AP31-3, 1 North Waukegan Rd., North Chicago, Illinois, 60064, USA.
Analytical Research & Development, AbbVie, Inc., North Chicago, Illinois, 60064, USA.
AAPS J. 2023 Mar 22;25(3):30. doi: 10.1208/s12248-023-00794-6.
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.
为了避免大型生物等效性研究，并避免让健康绝经后妇女因接受 Elagolix 联合激素补充疗法而暴露于额外的药物，我们使用基于生理学的药代动力学（PBPK）模型和体外溶出数据来测试虚拟生物等效性。对于子宫内膜异位症，Elagolix 的批准剂量为每日一次 150mg 和每日两次 200mg，作为片剂使用。作为联合疗法，在 3 期子宫内膜异位症试验中使用了两种单独的片剂，一种是 Elagolix 片剂，另一种是雌二醇/炔诺酮醋酸酯 1/0.5mg（E2/NETA）片剂。然而，商业联合药物产品由早晨胶囊（含有 Elagolix 片剂和 E2/NETA 片剂作为固定剂量组合胶囊，AM 胶囊）和晚上胶囊（含有 Elagolix 片剂，PM 胶囊）组成。片剂和胶囊制剂的体外溶出曲线不同；因此，需要进行体内生物等效性研究或豁免生物等效性。为了模拟交叉生物等效性试验，将体外溶出数据纳入之前验证过的 PBPK 模型中。使用相关的生物等效性研究数据对更新的 PBPK 模型进行了外部验证。基于虚拟生物等效性模拟的结果，与参比片剂相比，商业药物胶囊符合 0.80-1.25 的生物等效性标准。这是一个利用 PBPK 模型和体外溶出数据来证明虚拟生物等效性以支持监管生物等效性豁免的新颖示例。
