title: Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil.
abstract: Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.
authors: XenoPort, Inc, Santa Clara, CA, USA. ritu.lal@xenoport.com
authors: Ritu
authors: R
authors: Lal
authors: Juthamas
authors: J
authors: Sukbuntherng
authors: Wendy
authors: W
authors: Luo
authors: James
authors: J
authors: Tovera
authors: Marie Liesse
authors: ML
authors: Lassauzet
authors: Kenneth C
authors: KC
authors: Cundy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000588:Amines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012148:Restless Legs Syndrome / Q000097:blood / Q000188:drug therapy; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; 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; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin