title: Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses.
abstract: OBJECTIVE
  To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.
  
  
  METHODS
  Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.
  
  
  RESULTS
  Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T(max) was 4-6 h. Mean (SD) steady-state plasma C(max) and AUC(0-24) were 60 (25) ng ml(-1) and 1004 (303) ng h ml(-1), respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.
  
  
  CONCLUSIONS
  Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day(-1)) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.
authors.affiliation: Department of Clinical Pharmacology, University of Adelaide, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Rolan
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Eppie
authors.initials: E
authors.lastname: Chang
authors.forename: Drew
authors.initials: D
authors.lastname: Jones
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Gross
authors.forename: Jennifer Bahr
authors.initials: JB
authors.lastname: Davidson
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanftner
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002908:Chronic Disease; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012737:Sex Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles