Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil

• Published in: Journal of clinical pharmacology Vol. 53; no. 1; p. 29
• Main Authors: Lal, Ritu, Sukbuntherng, Juthamas, Luo, Wendy, Tovera, James, Lassauzet, Marie Liesse, Cundy, Kenneth C
• Format: Journal Article
• Language: English
• Published: England 01.01.2013
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Amines - administration & dosage; Amines - adverse effects; Amines - pharmacokinetics; Carbamates - administration & dosage; Carbamates - adverse effects; Carbamates - pharmacokinetics; Cyclohexanecarboxylic Acids - administration & dosage; Cyclohexanecarboxylic Acids - adverse effects; Cyclohexanecarboxylic Acids - pharmacokinetics; Female; gamma-Aminobutyric Acid - administration & dosage; gamma-Aminobutyric Acid - adverse effects; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - pharmacokinetics; Humans; Male; Middle Aged; Models, Biological; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Restless Legs Syndrome - blood; Restless Legs Syndrome - drug therapy; Sleep Initiation and Maintenance Disorders - blood; Sleep Initiation and Maintenance Disorders - drug therapy; Sleep Initiation and Maintenance Disorders - metabolism; Young Adult
• ISSN: 1552-4604
• DOI: 10.1177/0091270012439209

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.