title: Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects.
abstract: Tedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China.
  
  
  
  This Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study.
  
  
  
  The Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg • h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg • h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE.
  
  
  
  The results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Clinical Science China, Bayer, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Shen
authors.affiliation: Clinical Science China, Bayer, Beijing, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Chang
authors.affiliation: Clinical Pharmacology, Bayer Yakuhin, Osaka, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Global Medical Affairs, Bayer, Berlin, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing China. Electronic address: hubei@pumch.cn.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019540:Area Under Curve; D044466:Asian People; D001682:Biological Availability; D002681:China; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010080:Oxazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; C515040:tedizolid phosphate
keywords: healthy Chinese volunteers; multiple sequential administration; pharmacokinetics; safety; single administration; tedizolid