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.

Gabapentin enacarbil extended release for the treatment of postherpetic neuralgia in adults

“…The study mathematically predicted the probabilities that dizziness and somnolence would be lower than 5% for groups receiving doses of 600 mg and 1,200 mg 16. No appreciable differences were subsequently observed between these two dosing groups for dizziness or somnolence in this data set.…”

“…The Gp enacarbil (GpEn) formulation (developed under XP13512/GSK1838262; GlaxoKlineSmith, Brentford, UK) aims to do this by overcoming absorption limitations. It is an (acyloxy)alkyl carbamate prodrug of Gp, with an absorption profile stated to provide predictable bioavailability and sustained, dose-proportional drug exposure 16. Unlike GpIR, it is absorbed via mechanisms present throughout the intestine 14.…”

“…Unlike GpIR, it is absorbed via mechanisms present throughout the intestine 14. This plentiful absorptive target area makes the drug amenable to an extended release approach, and the GpEn preparation utilizes an erosion-based, extended release formula based on a wax matrix 16. Dosing of the medication is suggested at 600 mg twice daily (bd) for PHN, initiated at 600 mg once daily (in the morning) for 3 days, and then increased to bd (1,200 mg) on the fourth day 17…”

“…Absorption was by both passive and active mechanisms via high-capacity nutrient transporters, monocarboxylate transporter-1 and sodium-dependent multivitamin transporters. These transporters are known to be present throughout the upper and lower intestinal tract 16. Absorption and hydrolysis of the prodrug lead to Gp plasma concentrations increasing and declining in an exponential manner.…”

Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

“…Using plasma gabapentin concentration data obtained after administration of gabapentin enacarbil in 12 Phase I–III trials involving healthy adults (n=95) and patients with RLS (n=994; dose range, 300–2,400 mg/day), a population pharmacokinetic model was developed by nonlinear mixed-effect modeling using the software NONREM 58. Population pharmacokinetic-pharmacodynamic (PK-PD) models were also evaluated using gabapentin exposure and change from baseline in IRLS total score and investigator-/patient-rated CGI-I.…”