title: Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.
abstract: OBJECTIVE
  Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability.
  
  
  METHODS
  This randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs.
  
  
  RESULTS
  Of the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens.
  
  
  CONCLUSIONS
  No significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.
authors.affiliation: GlaxoSmithKline, Uxbridge, United Kingdom. Electronic address: chao.c.chen@gsk.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Upward
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Thangam
authors.initials: T
authors.lastname: Arumugham
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Brendt
authors.initials: B
authors.lastname: Stier
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Davy
mesh_terms: D000328:Adult; D000588:Amines / Q000493:pharmacokinetics; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D020920:Dyssomnias / Q000139:chemically induced; D004562:Electrocardiography / Q000187:drug effects; D000077206:Gabapentin; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009325:Nausea / Q000139:chemically induced; D011355:Prodrugs; 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; D000588:Amines; D000701:Analgesics, Opioid; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine
keywords: combination; gabapentin enacarbil; morphine; pharmacodynamics; pharmacokinetics