Gabapentin enacarbil – clinical efficacy in restless legs syndrome

Abstract

Restless legs syndrome (RLS) is a sleep-related movement disorder commonly involving an unpleasant urge to move the limbs, typically the legs. Dopaminergic agents represent the first-line therapy for RLS; however, long-term use of such drugs results in worsening symptoms due to “augmentation” or other adverse events. Gabapentin, an analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), is an anticonvulsant/analgesic agent. Gabapentin is only mildly effective in relieving RLS symptoms, perhaps a result of its poor absorption from the gastrointestinal (GI) tract. Gabapentin enacarbil is a prodrug of gabapentin specifically designed to enhance absorption via the GI tract, and hence provide improved circulating levels of gabapentin on metabolism. Clinical trials to date have demonstrated favorable safety and (compared to traditional gabapentin) improved pharmacokinetics and efficacy in treating RLS symptoms. Thus, gabapentin enacarbil may prove to be a useful drug in treating RLS. An application of gabapentin enacarbil for treatment of RLS is currently pending with FDA for approval.

Possible Sites of Therapeutic Action in Restless Legs Syndrome: Focus on Dopamine and α₂δ Ligands

“…In a small placebo-controlled study, gabapentin improved RLS symptoms, periodic leg movements during sleep, and sleep architecture in patients with RLS, most of whom had the idiopathic form [41] . Gabapentin enacarbil, a prodrug of gabapentin with improved pharmacokinetics [42] , significantly improved IRLS scores, clinicianrated response to therapy, and some sleep parameters in patients with idiopathic RLS [43][44][45][46] . In a small uncontrolled study of pregabalin in clinical practice, most patients with secondary RLS and neuropathic pain reported improvements in their RLS symptoms [47] .…”

Gabapentin Enacarbil: Pharmacotherapy of Restless Legs Syndrome

“…It is an effective anticonvulsant and analgesic however only minimally ameliorates RLS due to several pharmacokinetic limitations. Absorption occurs via a low-capacity solute transporter (most likely an L-type amino acid transporter) localized to the upper smaller intestine 1. This saturates as therapeutic quantities are delivered.…”

“…Drug bioavailability is reduced and continues to lessen as doses are increased. GBP is quickly excreted unaltered by the kidneys within the urine possessing a half-life ranging between five and seven hours 1. A limited half-life alongside an unpredictable bioavailability restricts use 3.…”

“…It is an identified substrate of two higher-capacity nutrient transporters: monocarboxylate transporter type I (MCT-1) and sodium-dependent multivitamin transporter (SMVT). Both are widely distributed along the entire human intestinal tract thus increase bioavailability 1. This greater transportation potential enables larger quantities of GE to be distributed within efficient dose proportions preventing saturation from occurring at therapeutic levels.…”

“…GBP has been effective for RLS sufferers however its use remains questionable due to an unknown underlying mechanism of action and several pharmacokinetic limitations, including an unpredictable bioavailability and limited half-life. The specifically manufactured prodrug Gabapentin Enacarbil (GE) possesses enhanced pharmacokinetics which overcome GBP’s limitations, possibly enabling more efficient RLS treatment 1. Research evaluating the efficacy alongside tolerability of GBP and GE will be presented, methodological quality examined and a conclusion established regarding GE’s place in practice.…”