title: Effect of ketoconazole on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor teneligliptin: an open-label study in healthy white subjects in Germany.
abstract: OBJECTIVE
  The aim of this study was to examine the effect of ketoconazole, a potent cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics and to evaluate the safety of combined administration of teneligliptin with ketoconazole.
  
  
  METHODS
  This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8-10), 400 mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13), ketoconazole was administered once daily. The pharmacokinetic parameters (Cmax, Tmax, AUC, terminal t½, apparent total plasma clearance, and Vd during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The safety profile was evaluated based on adverse events and clinical findings. To investigate the role of human P-gp in membrane permeation of teneligliptin, an in vitro study was performed to measure the transcellular transport of teneligliptin across monolayers of human P-gp-expressing cells and control cells.
  
  
  RESULTS
  For Cmax and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with ketoconazole to teneligliptin alone were 1.37 (1.25-1.50) and 1.49 (1.39-1.60), respectively. There was no change in t½ of the terminal elimination phase. In addition, the tolerability of teneligliptin coadministered with ketoconazole was acceptable. The in vitro study revealed corrected efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of 1 and 10 μM, respectively.
  
  
  CONCLUSIONS
  Because the exposure to teneligliptin in combined administration with ketoconazole, a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of teneligliptin alone, it is suggested that combined administration of teneligliptin with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure. The results of our in vitro study suggest that teneligliptin is a substrate of P-gp.
  
  
  BACKGROUND
  EudraCT No. 2009-016652-51.
authors.affiliation: DMPK Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan. Electronic address: nakamaru.yoshinobu@mf.mt-pharma.co.jp.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nakamaru
authors.affiliation: Project Management Department, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Development Regulatory Affairs Department, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Sekine
authors.affiliation: Clinical Pharmacology Department, Data Science Center, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kinoshita
authors.affiliation: Mitsubishi Pharma Europe Ltd, London, United Kingdom.
authors.forename: Jeff
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Clinical Pharmacology Department, Data Science Center, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kawaguchi
authors.affiliation: Mitsubishi Pharma Europe Ltd, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Davies
authors.affiliation: Nuvisan GmbH, Neu-Ulm, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Jürgen Heuer
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: DMPK Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Akimoto
mesh_terms: D000293:Adolescent; D000328:Adult; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005858:Germany; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D053778:Thiazolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011720:Pyrazoles; D053778:Thiazolidines; D007654:Ketoconazole
keywords: dipeptidyl peptidase-4 inhibitor; drug–drug interactions; ketoconazole; pharmacokinetics; teneligliptin