title: Pharmacokinetics, safety and tolerability of mipomersen in healthy Japanese volunteers and comparison with Western subjects.
abstract: OBJECTIVE
  To characterize the safety, tolerability, pharmacokinetics (PK) and dose proportionality of mipomersen after single subcutaneous (SC) administration to Japanese healthy subjects; and to compare the PK profiles of Japanese and Western subjects.
  
  
  METHODS
  20 healthy first-generation Japanese male subjects were enrolled into one of three treatment cohorts (50, 100 and 200 mg SC) in a dose-escalation design. Within each cohort, subjects were randomized in a 4 : 1 ratio to receive mipomersen or placebo.
  
  
  RESULTS
  Mipomersen was absorbed rapidly after SC administration; median tmax varied between 2 and 3 hours. After reaching peak levels, plasma concentrations of mipomersen decayed multiphasically with an initial distribution t1/2 in several hours and a terminal t1/2 of 261 - 393 hours. Mean Cmax increased in a dose-linear manner while all mean AUC from time 0 to different cut points increased slightly more than dose proportionally. Although mean terminal t1/2 varied in the dose range tested, it did not show dose-dependence. The PK profiles of mipomersen in Japanese subjects are similar to those observed in Western subjects. A single SC dose of 50 mg, 100 mg and 200 mg mipomersen was well tolerated by male Japanese subjects.
  
  
  CONCLUSIONS
  Single SC doses of 50 - 200 mg were safe and well tolerated when administered to Japanese subjects. Comparison of PK between Japanese and Western subjects does not support any need for dose adjustment in Japanese population in future clinical development.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Marjie L
authors.initials: ML
authors.lastname: Hard
authors.forename: Grit
authors.initials: G
authors.lastname: Andersen
authors.forename: Günther
authors.initials: G
authors.lastname: Pabst
authors.forename: Gilbert
authors.initials: G
authors.lastname: Wagener
authors.forename: Tejdip
authors.initials: T
authors.lastname: Singh
authors.forename: Wai
authors.initials: W
authors.lastname: Chin
authors.forename: Kerry
authors.initials: K
authors.lastname: Culm-Merdek
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boltje
authors.forename: Lisa L
authors.initials: LL
authors.lastname: von Moltke
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009841:Oligonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies
chemical_list: D009841:Oligonucleotides; C524142:mipomersen