Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Clin Pharmacokinet. 2017 Nov;56(11):1415-1427. doi: 10.1007/s40262-017-0531-7.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated.
In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated.
Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C (t ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR); however, a 2% increase in area under the INR curve (AUC) was observed.
Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen are recommended when coadministered with dulaglutide.
NCT01458210, NCT01436201, NCT01432938, and NCT01250834.
胰高血糖素样肽-1 受体激动剂（GLP-1 RAs）用于治疗 2 型糖尿病，已知可延缓胃排空（GE）。研究了 GLP-1 RA 度拉鲁肽对四种口服药物的药代动力学（PK）和华法林药效学（PD）的潜在影响。
在四项单独的临床药理学研究中，地高辛、华法林、阿托伐他汀和 Ortho-Cyclen 在健康受试者中口服给予和不给予皮下剂量 1.5mg 度拉鲁肽。基于关键分析物的 PK 参数评估度拉鲁肽合用的效果。对于华法林 PD，评估了度拉鲁肽对华法林国际标准化比值（INR）的影响。
除阿托伐他汀外，所有分析物的 AUC 均与无度拉鲁肽时相似，阿托伐他汀的 AUC 降低了 21%。与度拉鲁肽合用后，C 的最大值（C ）通常较低，除 R-华法林外，所有分析物的几何最小平方均值比值（90%置信区间不在 0.80-1.25 范围内）均有统计学意义降低。对于所有分析物，与度拉鲁肽合用后，C （t ）达到最大值的时间普遍增加。对于华法林，度拉鲁肽合用对最大 INR（INR）没有统计学显著影响；然而，观察到 INR 曲线下面积（AUC）增加了 2%。
度拉鲁肽对所测试药物的吸收没有产生临床相关程度的影响。基于 PK 和 PD 评估，当与度拉鲁肽合用时，不建议对华法林、地高辛、阿托伐他汀和 Ortho-Cyclen 进行剂量调整。
NCT01458210、NCT01436201、NCT01432938 和 NCT01250834。
