title: Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.
abstract: OBJECTIVE
  To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Therapeutic Area Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: E U
authors.initials: EU
authors.lastname: Graefe-Mody
authors.forename: T
authors.initials: T
authors.lastname: Brand
authors.forename: A
authors.initials: A
authors.lastname: Ring
authors.forename: B
authors.initials: B
authors.lastname: Withopf
authors.forename: J
authors.initials: J
authors.lastname: Stangier
authors.forename: M
authors.initials: M
authors.lastname: Iovino
authors.forename: H-J
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology*; D012984:Software; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D014859:Warfarin / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases