评估新研究化合物的药物相互作用 (DDI) 需要进行多项试验来评估具有不同转运蛋白特异性的不同药物。通过使用具有不同转运蛋白特异性的药物混合物，一次试验可以同时评估每种混合物药物的药代动力学 (PK)，从而减少临床开发所需的临床 DDI 试验数量。我们的目的是研究稳态勃林格殷格翰 (BI) 730357 (bevurogant) 对经过验证和优化的 4 组分转运蛋白混合物的 PK 的影响。这项开放标签、非随机、2 周期固定序列 I 期试验在 18 岁以下健康受试者中比较了使用或不使用 BI 730357 的转运蛋白混合物（0.25 mg 地高辛/1 mg 呋塞米/10 mg 盐酸二甲双胍/10 mg 瑞舒伐他汀）。 55 岁，体重指数 18.5-29.9 kg/m2。在参考治疗/第 1 阶段期间，早餐后 90 分钟给予转运蛋白鸡尾酒。清洗期后，在测试治疗/第 2 期期间，每日两次给予 BI 730357，持续 13 天，并在第 1 天给予转运蛋白混合物。主要终点是血浆中分析物随时间变化的浓度-时间曲线下面积从 0 外推到无穷大的间隔 (AUC0-∞ ) 和血浆中分析物的最大测量浓度 (Cmax )，次要终点是血浆中分析物在从 0 到 0 的时间间隔内的浓度-时间曲线下面积最后一个可量化的数据点 (AUC0-tz )。稳态 BI 730357 增加了地高辛（48% 至 94%）、二甲双胍（-2% 至 -9%）、呋塞米（12% 至 18%）和瑞舒伐他汀（19% 至 39%）的暴露量。因此，没有观察到转运蛋白 OCT2/MATE-1/MATE-2K、OAT1/OAT3、OATP1B1/OATP1B3 的临床相关抑制。粪卟啉 I/III（OATP1B1/OATP1B3 生物标志物）的 PK 参数对乳腺癌耐药蛋白的潜在抑制作用保持在生物等效性边界内，而瑞舒伐他汀 PK 参数 (AUC0-∞ /Cmax /AUC0-tz ) 超出了生物等效性边界。 BI 730357 安全且耐受性良好。该试验证实了由地高辛、呋塞米、二甲双胍和瑞舒伐他汀组成的转运蛋白混合物在评估体内药物转运蛋白相互作用方面的有用性和耐受性。© 2023，美国临床药理学会。

Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail. This open-label, non-randomized, 2-period fixed-sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18-55 years with body mass index 18.5-29.9 kg/m2 . During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) and the maximum measured concentration of the analyte in plasma (Cmax ), and the secondary endpoint was the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz ). Steady-state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (-2% to -9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE-1/MATE-2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0-∞ /Cmax /AUC0-tz ) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug-transporter interactions in vivo.© 2023, The American College of Clinical Pharmacology.