Gabapentin Enacarbil - Drug Monograph
Introduction
Gabapentin enacarbil is a prodrug of gabapentin specifically designed to overcome the saturable absorption limitations of conventional gabapentin formulations. Marketed under the brand name Horizant®, it was developed to provide more predictable pharmacokinetics and improved bioavailability for the management of certain neurological conditions. This extended-release formulation represents an important advancement in gabapentin therapy, particularly for conditions requiring sustained drug delivery.
Mechanism of Action
Gabapentin enacarbil is a prodrug that undergoes rapid hydrolysis by nonspecific esterases in the intestinal lumen and enterocytes to form gabapentin. The active moiety, gabapentin, is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but does not act directly on GABA receptors. Its exact mechanism remains incompletely understood but is believed to involve binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This binding modulates calcium influx into neurons, reducing the release of several neurotransmitters, including glutamate, norepinephrine, and substance P, which may contribute to its therapeutic effects in neuropathic pain and restless legs syndrome.
Indications
Gabapentin enacarbil is FDA-approved for:
- Treatment of moderate-to-severe primary Restless Legs Syndrome (RLS)
- Management of postherpetic neuralgia (PHN)
It is important to note that gabapentin enacarbil is not interchangeable with other gabapentin products due to differences in pharmacokinetics.
Dosage and Administration
Restless Legs Syndrome: 600 mg once daily taken at about 5 PM Postherpetic Neuralgia: 600 mg twice daily (1200 mg total daily dose) Administration:- Must be taken with food
- Tablets should be swallowed whole and not crushed, chewed, or divided
- Dose adjustment required in renal impairment:
- CrCl 30-59 mL/min: RLS 300 mg daily; PHN 600 mg daily - CrCl 15-29 mL/min: RLS 300 mg daily; PHN 300 mg daily - CrCl <15 mL/min: Not recommended
- Not recommended for patients requiring hemodialysis
Pharmacokinetics
Absorption: Gabapentin enacarbil is absorbed via monocarboxylate transporter 1 (MCT-1) in a nonsaturable process, resulting in dose-proportional pharmacokinetics with approximately 68% bioavailability as gabapentin. Distribution: Gabapentin is widely distributed throughout the body and crosses the blood-brain barrier. Volume of distribution is approximately 50-60 L. Protein binding is negligible (<3%). Metabolism: Rapidly converted to gabapentin by esterases in the intestinal wall and liver. Gabapentin itself is not metabolized to a significant extent. Elimination: Gabapentin is eliminated unchanged primarily by renal excretion via glomerular filtration. Elimination half-life is 5-7 hours. Total clearance correlates with creatinine clearance.Contraindications
- Hypersensitivity to gabapentin or any component of the formulation
- Patients with severe renal impairment (CrCl <15 mL/min) or on hemodialysis
Warnings and Precautions
Suicidal Behavior and Ideation: Antiepileptic drugs increase the risk of suicidal thoughts or behavior. DRESS Syndrome: Drug Reaction with Eosinophilia and Systemic Symptoms has been reported; discontinue if signs appear. Respiratory Depression: May cause serious respiratory depression, especially when used with CNS depressants or in patients with respiratory compromise. Neuropsychiatric Adverse Reactions: May cause somnolence, dizziness, and impairment in driving ability. Withdrawal Symptoms: Abrupt discontinuation may precipitate withdrawal symptoms including anxiety, insomnia, nausea, pain, and sweating. Tumorigenic Potential: Pancreatic acinar cell tumors observed in rats; clinical significance unknown.Drug Interactions
CNS Depressants: Enhanced sedative effects with alcohol, opioids, benzodiazepines, and other CNS depressants. Antacids: Magnesium/aluminum-containing antacids may reduce bioavailability; separate administration by at least 2 hours. Morphine: May increase gabapentin concentrations; monitor for increased CNS depression.Adverse Effects
Common (≥5%): Dizziness, somnolence, headache, fatigue Serious:- Suicidal ideation and behavior
- Respiratory depression
- Angioedema
- DRESS syndrome
- Withdrawal symptoms upon abrupt discontinuation
- Peripheral edema
Monitoring Parameters
- Renal function at baseline and periodically during treatment
- Mental status and mood changes, particularly for emergence of depression or suicidal thoughts
- Signs of CNS depression, especially when co-administered with other sedating medications
- Clinical response and adverse effects
- Signs of hypersensitivity reactions
Patient Education
- Take medication exactly as prescribed with food
- Do not crush, chew, or break tablets
- Be aware of potential dizziness and drowsiness; avoid driving or operating machinery until effects are known
- Do not abruptly discontinue medication without medical supervision
- Avoid alcohol and other CNS depressants
- Report any mood changes, depression, or suicidal thoughts immediately
- Inform all healthcare providers about gabapentin enacarbil use
- Keep medication out of reach of children
References
1. FDA Prescribing Information: Horizant® (gabapentin enacarbil) Extended-Release Tablets 2. Bockbrader HN, et al. Clin Pharmacokinet. 2010;49(9):601-614 3. Lal R, et al. J Clin Pharmacol. 2009;49(12):1432-1440 4. Kushida CA, et al. Sleep Med. 2009;10(5):494-502 5. Gidal BE, et al. Epilepsy Res. 1998;29(3):233-241 6. Pande AC, et al. J Clin Psychopharmacol. 2000;20(4):467-471 7. US National Library of Medicine: DailyMed - Horizant label information 8. UpToDate: Gabapentin drug information 9. Micromedex Solutions: Gabapentin enacarbil monograph