title: Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.
abstract: A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.
authors.affiliation: Dept of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Dept of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan hiro-tosei-lung@kkd.biglobe.ne.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Graduate School of Medicine Nippon Medical School, Tokyo, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Azuma
authors.affiliation: Dept of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Dept of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Dept of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Division of Pulmonary Medicine, Dept of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Bando
authors.affiliation: Graduate School of Medicine Nippon Medical School, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Abe
authors.affiliation: Respiratory Medicine, Himeji Medical Center, Himeji, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Mochizuki
authors.affiliation: Second Division, Dept of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kingo
authors.initials: K
authors.lastname: Chida
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klüglich
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Okazaki
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tadayasu
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sakamoto
authors.affiliation: Division of Pulmonary Medicine, Dept of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014797:Vital Capacity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007211:Indoles; D011728:Pyridones; C093844:pirfenidone; C530716:nintedanib