title: A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics.
abstract: BACKGROUND
  Abrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome.
  
  
  OBJECTIVE
  To evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses.
  
  
  METHODS
  Randomized, open-label, dose-escalation, crossover study.
  
  
  METHODS
  Contract Research Organization (CRO).
  
  
  METHODS
  Three cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period.
  
  
  METHODS
  Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis.
  
  
  RESULTS
  None of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (Cmax). After the 20 mg PO and 15 mg IV doses, mean Cmaxlevels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%.
  
  
  CONCLUSIONS
  All PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible.
  
  
  METHODS
  II.
authors.affiliation: Center for Orphan Drug Research, Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN(∗).
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Schmitz
authors.affiliation: Courage Kenny Rehabilitation Institute, Part of Allina Health, Minneapolis, MN(†).
authors.forename: Linda E
authors.initials: LE
authors.lastname: Krach
authors.affiliation: Center for Orphan Drug Research, Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN(‡).
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Coles
authors.affiliation: Center for Orphan Drug Research, Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN(§).
authors.forename: Usha
authors.initials: U
authors.lastname: Mishra
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Abbvie Inc, North Chicago, IL(‖).
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Center for Orphan Drug Research, Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis, MN(¶).
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
authors.affiliation: Center for Orphan Drug Research, Experimental & Clinical Pharmacology, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455(#). Electronic address: kriel001@umn.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kriel
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001418:Baclofen / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D055815:Young Adult
chemical_list: D001418:Baclofen