Generic Name

Gabapentin enacarbil

Mechanism

• Prodrug conversion: After oral absorption, gabapentin enacarbil is hydrolyzed by esterases (primarily the intestinal brush‑border enzyme, *carboxylesterase 1*) to release free gabapentin.
• α2δ‑1 subunit modulation: Gabapentin binds with high affinity to the α2δ‑1 subunit of voltage‑gated calcium channels in the central nervous system, reducing calcium influx.
• Decreased excitatory neurotransmission: This inhibition lowers the release of glutamate, norepinephrine, and substance P, leading to attenuation of neuronal hyperexcitability.

Pharmacokinetics

• Absorption: ~70 % bioavailable when administered on an empty stomach; absorption is saturable, with a maximum rate around 9 mg/kg IV (dose‑dependent).
• Distribution: Extensively distributed in plasma, with a volume of distribution ~0.5 L/kg. No significant protein binding.
• Metabolism: Primarily hydrolyzed to gabapentin by esterases; no active metabolites.
• Elimination: Renally excreted unchanged; half‑life ~5–13 h (varies 6–10 h in adults). Clearance increased in patients with impaired renal function.
• Special populations: Dose adjustment required for severe renal impairment; no dose adjustment for mild‑moderate hepatic dysfunction.

Indications

• Post‑herpetic neuralgia (PHN) – adjunctive therapy for chronic neuralgic pain following shingles.
• Diabetic peripheral neuropathic pain – long‑term management of distal neuropathic pain in diabetes.
• Idiopathic neuropathic pain – when gabapentin is considered but once‑daily convenience is desired.

Contraindications

• Allergy: Hypersensitivity to gabapentin, enacarbil, or any excipients.
• Renal impairment: Severe impairment (creatinine clearance <15 mL/min) warrants dose reduction; monitor renal function.
• Drug interactions: Concomitant use with medications that undergo the same renal clearance or cause additive CNS depression (e.g., opioids, benzodiazepines) may increase risk of sedation.
• Pregnancy: Category C; use only if potential benefit outweighs risk.
• Breastfeeding: Limited data; caution advised.

Dosing

• Administration: Take on an empty stomach for optimal absorption; optional co‑administration with food may slightly decrease bioavailability but is acceptable if needed for gastrointestinal comfort.
• Switching from extended‑release gabapentin: Maintain total daily dose; ensure no overlapping exposures.

Adverse Effects

*Adverse events are dose‑related; gradual titration mitigates most symptoms.*

Monitoring

• Renal function: Serum creatinine and eGFR prior to initiation and periodically (every 3–6 months) for long‑term therapy.
• Blood pressure: Observe for orthostatic hypotension, though rare.
• Neurological status: Assess for worsening pain, sedation, or ataxia.
• Adherence: Confirm once‑daily compliance to avoid breakthrough pain and subtherapeutic levels.

Clinical Pearls

• Prodrug advantage: The ester linkage of gabapentin enacarbil delays peak plasma levels, reducing peak‑to‑trough variability and helping to avoid nighttime somnolence common with immediate‑release gabapentin.
• Empty‑stomach requirement: While food delays absorption, it does not reduce total bioavailability; give on an empty stomach only when rapid onset is needed (e.g., breakthrough pain episodes).
• Renal dosing is linear: For every 20 % decline in creatinine clearance, decrease the maintenance dose by ~20 % (e.g., 2,400 mg → 1,920 mg q.d. in mild CKD).
• Combination with opioids: Monitor closely—gabapentin enacarbil can augment opioid‑induced respiratory depression; consider a lower opioid dose or use a dedicated opioid‑sparing protocol.
• Examine for edema: Peripheral edema can be misattributed to fluid overload; it may improve quickly with dose reduction or diuretic therapy.
• Patient education: Emphasize the importance of not abruptly stopping therapy to avoid rebound hyperexcitability and pain flare‑ups.

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• *All data are current as of 2026-01-02. For individualized therapy, consult the latest prescribing information and institutional guidelines.*