Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Division of Clinical Pharmacology, Department of Medicine, The University of Western Ontario, London, ON, Canada.
Pharm Res. 2023 Nov;40(11):2499-2511. doi: 10.1007/s11095-022-03464-y. Epub 2023 Jan 12.
The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling.
LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs.
In vitro inhibitory potencies (IC) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid.
OAT1- mediated DDIs can be predicted using in vitro measured IC and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.
本研究旨在证明临床 OAT1 介导的药物相互作用可通过基于生理的药代动力学（PBPK）模型进行预测。
LY404039 是一种代谢型谷氨酸受体 2/3 激动剂，也是前药培莫沙明（LY2140023）的活性部分。口服给药后，培莫沙明通过 PEPT1 被肠上皮细胞快速摄取，一旦吸收，通过膜二肽基肽酶 1（DPEP1）转化为 LY404039。LY404039 通过肾小球滤过和主动分泌两种方式从肾脏排泄，体外研究表明 LY404039 的主动分泌由有机阴离子转运体 1（OAT1）介导。临床和体外数据均用于构建 PBPK 模型以预测 OAT1 介导的药物相互作用。
测定了已知 OAT 抑制剂丙磺舒和布洛芬的体外抑制效力（IC），分别为 4.00 和 2.63µM。随后，临床药物相互作用（DDI）研究表明丙磺舒使 LY404039 的肾清除率降低了 30%至 40%。基于底层的 PBPK 模型预测的肾清除率比观察到的低约 20%。使用 OAT1 相对活性因子（RAF）为 3 的中间模型，准确地再现了 LY404039 的肾清除率和丙磺舒存在时 LY404039 的药代动力学（PK）变化。
可以通过体外测定的 IC 和 PBPK 模型预测 OAT1 介导的药物相互作用。布洛芬的影响预计很小（AUC 比值为 1.15），且无临床相关性。
