title: Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers.
abstract: BACKGROUND
  Gabapentin enacarbil is an actively transported prodrug of gabapentin that provides predictable dose-proportional gabapentin exposure with high (> or =68%) oral bioavailability.
  
  
  OBJECTIVE
  The aims of this study were to investigate the pharmacokinetics and tolerability of gabapentin enacarbil up to supratherapeutic doses and the effects of gabapentin enacarbil on cardiac repolarization in healthy volunteers, and to provide a dose reference for a future definitive QT/corrected QT (QTc) study.
  
  
  METHODS
  This was a randomized-sequence, double-blind, placebo-controlled, single escalating-dose, crossover study of gabapentin enacarbil 600-mg extended-release tablets administered as a single oral dose of 2400, 3600, 4800, or 6000 mg or placebo, with a 1-week washout between administrations. Blood samples were collected over a period of 36 hours after administration and were analyzed using a validated method of liquid chromatography/tandem mass spec-trometry. Blood gabapentin enacarbil and gabapentin concentrations were analyzed using noncompartmental methods. Tolerability was assessed by monitoring adverse events (AEs) (using subject interview/reporting), laboratory parameters, vital sign measurements, and 12-lead electrocardiography (ECG). Holter ECG was also performed.
  
  
  RESULTS
  Thirty-two healthy volunteers were included in the study (18 women, 14 men; mean [SD] age, 31.2 [11.4] years; body mass index, 24.9 [3.04] kg/m(2)). Gabapentin enacarbil was converted rapidly to gaba-pentin after absorption. Gabapentin exposure in blood was proportional to gabapentin enacarbil dose over the range of 2400 to 6000 mg (1250-3125 mg-equivalent gabapentin). Blood concentrations of intact gabapen-tin enacarbil were low and transient (< or =0.5% of the released gabapentin concentration at all doses). The most commonly reported AEs were dizziness and nausea (50% and 25% of subjects, respectively). All but 4 AEs were mild to moderate in intensity. Two subjects experienced treatment-emergent AEs rated as severe: psychomotor retardation, vertigo, and sedation (4800-mg dose) and somnolence (6000 mg). All treatment-emergent AEs resolved without medical intervention. No serious AEs were reported, and none of the AEs led to study withdrawal. There were no clinically significant changes in laboratory parameters, vital sign measurements, or ECG values; QTc intervals did not exceed 480 msec or change from baseline >30 msec at any gabapentin enacarbil dose.
  
  
  CONCLUSIONS
  Gabapentin enacarbil was associated with dose-proportional gabapentin exposure at doses up to 6000 mg and was generally well tolerated in these healthy subjects. These findings support the use of 6000-mg gabapentin enacarbil in a definitive QT/QTc study.
authors.affiliation: XenoPort, Inc., Santa Clara, California 95051, USA. ritu.lal@xenoport.com
authors.forename: Ritu
authors.initials: R
authors.lastname: Lal
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.forename: Wendy
authors.initials: W
authors.lastname: Luo
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.forename: Amanda
authors.initials: A
authors.lastname: Vu
authors.forename: James
authors.initials: J
authors.lastname: Tovera
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Cundy
mesh_terms: D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs; D053719:Tandem Mass Spectrometry; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D000700:Analgesics; D000927:Anticonvulsants; D002219:Carbamates; D003692:Delayed-Action Preparations; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid