Graefe-Mody E U, Brand T, Ring A, Withopf B, Stangier J, Iovino M, Woerle H-J
Therapeutic Area Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Int J Clin Pharmacol Ther. 2011 May;49(5):300-10. doi: 10.5414/cp201507.
To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate.
This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose.
The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-∞ and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated.
Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin.
研究利格列汀估计最高治疗剂量（5毫克）对细胞色素P450 2C9（CYP2C9）底物华法林的药代动力学和药效学的影响。
本开放标签、两阶段、固定顺序试验纳入了18名健康男性志愿者，其中17名是CYP2C9*1/*1纯合子。受试者接受单次口服华法林剂量（10毫克），随后有至少14天的洗脱期。然后受试者每天口服一次利格列汀5毫克，共12天（即达到稳态），在第6天给予单次剂量的华法林（10毫克）。在给药前以及给药后长达168小时测定R（+）华法林、S（-）华法林、凝血酶原时间（PT）和国际标准化比值（INR）。
对于R-华法林，（利格列汀+华法林）/华法林的AUC0-∞和Cmax的几何平均比值（GMRs）（90%置信区间（CI））分别为98.5（95.7 - 101.5）和99.7（94.7 - 104.9）；对于S-华法林，分别为103.0（99.1 - 107.0）和100.9（93.7 - 108.6）。利格列汀与华法林联合给药对INR或PT的AUC0-168没有临床相关影响。（利格列汀+华法林）/华法林的INR和PT AUC0-168的GMRs（90% CI）分别为93.4（86.2 - 101.1）和103.2（95.4 - 111.6）。与单独使用华法林相比，利格列汀与华法林联合给药后INR和PT的相应Eax值略有增加，分别为104.3（85.2 - 127.6）和15.1（94.3 - 140.6），这反映了这些终点指标变异性较高。利格列汀与华法林联合给药耐受性良好。
利格列汀与华法林联合给药不会改变R-或S-华法林的药代动力学或药效学，表明与利格列汀联合使用时无需调整华法林剂量。
