Drug Monitoring and Pharmacokinetics of

GabapentinPharm.İsa BADUR

ATC: N03AX12

Pharmacologic Category/ uses• Anticonvulsant, Miscellaneous; GABA Analog• Gabapentin is a highly lipophilic amino acid structurally similar to

GABA

• USES: Gabapentin is approved by the US Food and Drug Administration (FDA) for the treatment of partial seizures (with and without secondary generalization) and postherpetic neuralgia. Gabapentin is also used for the treatment of diabetic peripheral neuropathy, migraines, pain disorders, and various mood and movement disorders (non-FDA labeled indications)

Mechanism of Action • Gabapentin is structurally related to GABA. However, it does not bind

to GABAA or GABAB receptors, and it does not appear to influence synthesis or uptake of GABA. • High affinity gabapentin binding sites have been located throughout

the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. • This channel appears to be located presynaptically, and may modulate

the release of excitatory neurotransmitters which participate in epileptogenesis and nociception.

Dosing: Adult• Postherpetic neuralgia: Oral

• Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times daily; dose may be titrated as needed for pain relief (range: 1,800 to 3,600 mg/day in divided doses, daily doses >1,800 mg do not generally show greater benefit)

Seizures, partial onset• Initial: 300 mg 3 times daily; increase dosage based on response and

tolerability; usual dosage: 900 to 1,800 mg/day administered in 3 divided doses; doses of up to 2,400 mg/day have been tolerated in long-term clinical studies; up to 3,600 mg/day has been tolerated in short-term studies

• Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week.

Diabetic neuropathy (off-label use): • Oral: Immediate release: 900 to 3,600 mg/day, Bril 2011(1)

Hot flashes (off-label use): • Oral: Immediate release: Day 1: 300 mg at bedtime, Day 2: 300 mg

twice daily, followed by 300 mg 3 times/day for 4 weeks and then tapered off, Butt 2008(2)

Neuropathic pain (off-label use): • Oral: Immediate release: 300 to 3,600 mg/day, Attal 2010 (3);

Dworkin 2010 (4)

Neuropathic pain, critically ill patients (off-label use)• Oral: Immediate release: Initial: 100 mg 3 times daily in combination

with IV opioids; maintenance: 300 to 1,200 mg 3 times daily; maximum dose: 3,600 mg daily, Barr 2013 (5)

Postoperative pain (adjunct; off-label use) • Oral: Immediate release: 300 to 1,200 mg given the night before, 1 to

2 hours prior to surgery or immediately following surgery, Doleman 2015 (6); Peng 2007 (7); Yu 2013 (8)

Restless legs syndrome (RLS) (off-label use) • Oral: Immediate release: Initial: 300 mg once daily 2 hours before

bedtime. Doses ≥600 mg/day have been given in 2 divided doses (late afternoon and 2 hours before bedtime). Dose may be titrated every 2 weeks until symptom relief achieved (range: 300 to 1,800 mg/day). Suggested maintenance dosing schedule: One-third of total daily dose given at 12 pm, remaining two-thirds total daily dose given at 8 pm. Garcia-Borreguero 2002(9); Happe 2003 (10); Saletu 2010 (11); Vignatelli 2006 (12)

Social anxiety disorder (off-label use) • Oral: Initial: 300 mg twice daily; increase dose based on response and

tolerability in increments of no more than 300 mg/day up to a maximum of 3,600 mg/day given in 3 divided doses. Doses for responders ranged from 900 to 3,600 mg/day in the clinical trial ,Pande 1999 (13). • Additional data may be necessary to further define the role of

gabapentin in this condition.

Dosing: Pediatric-Seizures, partial onset• Children 3 to 4 years: Oral Initial: 10 to 15 mg/kg/day in 3 divided

doses; titrate to effective dose over ~3 days; increase dosage based on response and tolerability; usual dosage: 40 mg/kg/day in 3 divided doses; dosages of up to 50 mg/kg/day have been tolerated in clinical studies

Children 5 to 11 years• Oral Initial: 10 to 15 mg/kg/day in 3 divided doses; titrate to effective

dose over ~3 days; increase dosage based on response and tolerability; usual dosage: 25 to 35 mg/kg/day in 3 divided doses; dosages of up to 50 mg/kg/day have been tolerated in clinical studies

Children ≥12 years+Geriatric • Refer to adult dosing.

Oligopharmacy• If gabapentin is discontinued or if another anticonvulsant is added to

therapy, it should be done slowly over a minimum of 1 week

Renal Impairment Children ≥12 years and Adults

• CrCl ≥60 mL/minute: 300 to 1,200 mg 3 times daily

• CrCl >30 to 59 mL/minute: 200 to 700 mg twice daily

• CrCl >15 to 29 mL/minute: 200 to 700 mg once daily

• CrCl 15 mL/minute: 100 to 300 mg once daily

• CrCl <15 mL/minute: Reduce daily dose in proportion to creatinine clearance based on dose for creatinine clearance of 15 mL/minute (eg, reduce dose by one-half [range: 50 to 150 mg/day] for CrCl 7.5 mL/minute)

• ESRD (end stage renal disease) requiring hemodialysis: Dose based on CrCl plus a single supplemental dose of 125 to 350 mg (given after each 4 hours of hemodialysis)

Pharmacokinetics

Drug Concentration Levels• A) Therapeutic Drug Concentration• 1) Partial Seizures, greater than 2 mcg/mL [14].• a) The plasma concentration should be greater than 2 mcg/mL for

control of partial seizures [14].

Absorption • Variable, from proximal small bowel by L-amino transport system;

saturable process; dose-dependent

• Tmax, once-daily formulation: 8 hours [*]• Tmax, immediate-release: 2 hours [*]• Effect of food: increase rate and extent of absorption compared with

fasting state [*]

• [*] Product Information: GRALISE(R) oral tablets, gabapentin oral tablets. Abbott Laboratories, North Chicago, IL, 2011

Distribution • Vd: 58 ± 6 L; CSF concentrations are ~20% of plasma concentrations

• Protein binding: <3%

• Vd, adults: 58 L [*]• Vd, children: 1.8 to 2.76 L/kg [*]• Protein binding: less than 3% (15)

Metabolism • Not metabolized

• Excreted unchanged in the urine [16]

Bioavailability

• Inversely proportional to dose due to saturable absorption: Immediate release:

• 900 mg/day: 60%

• 1,200 mg/day: 47%

• 2,400 mg/day: 34%

• 3,600 mg/day: 33%

• 4,800 mg/day: 27%

Half-life elimination

• Infants 1 month to Children 12 years: 4.7 hours• pediatrics, 4.44 hours (16)• Adults, normal: 5 to 7 hours (17)• increased half-life with decreased renal function; anuric adult

patients: 132 hours; adults during hemodialysis: 3.8 hours• renal impairment, median, 9.2 to 40 hours; mean, 6.5 to 52 hours (18)

Time to peak • Immediate release: Infants 1 month to Children 12 years: 2 to 3 hours; Adults: 2 to 4 hours Peak Concentration• 1) Oral, multiple-dose: 1800 mg daily (once-daily formulation): 9585 nanograms/mL [19]• a) In a pharmacokinetic study (n=21), the mean Cmax of gabapentin was 9585 +/- 2326

nanograms/mL following administration of gabapentin tablets (once-daily formulation) 1800 mg daily for 5 days with a high fat meal (50% of calories from fat) [19].

• 2) Oral, multiple-dose: 600 mg three times daily (immediate-release): 8536 nanograms/mL [19]• a) In a pharmacokinetic study (n=21), the mean Cmax of gabapentin was 8536 +/- 1715

nanograms/mL following administration of gabapentin 600 mg immediate-release tablets three times daily for 5 days with a high fat meal (50% of calories from fat) [19].

Excretion –Kidney- Renal Clearance (rate)

• Proportional to renal function; urine (as unchanged drug)a) 150 mL/minute [15].• The renal clearance of gabapentin was 150 mL/min [15].b) Renal impairment, 10 to 90 mL/min [18][19]• Following administration of a single dose of gabapentin 400 mg immediate-release

(n=60), the renal clearance was 79 mL/min among patients with mild renal impairment (CrCl of at least 60 mL/min), 36 mL/min in moderate renal impairment (CrCl 30 to 59 mL/min), and 11 mL/min in severe renal impairment (CrCl less than 30 mL/min) [19].

• Following administration of a single dose of gabapentin 400 mg immediate-release (n=60), the renal clearance was approximately 90 mL/min in patients with CrCl of greater than 60 mL/min, and 10 mL/min in patients with CrCl less than 30 mL/min [18].

Excretion• c) Pediatrics, 4.41 to 7.40 mL/min/kg [16]• Renal clearance rates were 7.40 mL/min/kg and 4.41 mL/min/kg after

a single oral dose in children ages 1 month to under 5 years (n=27) and 5 to 12 years (n=21), respectively. Dosing for those 2 years or younger was gabapentin syrup 10 mg/kg; subjects over 2 years received oral capsules based on weight: 200 mg for 16 to 25 kg; 300 mg for 26 to 36 kg; 400 mg for 37 to 50 kg [16].

Excretion –Renal Excretion (%)

• a) Renal Excretion 76% to 81% [15].• Following administration of gabapentin, 76% to 81% was excreted in

the urine [15].• b) Children, 41.1% unchanged [16]• Percentage of dose excreted unchanged in the urine was 41.1% after

a single oral dose in children 5 to 12 years old (n=21). Dosing of oral capsules was based on weight: 200 mg for 16 to 25 kg; 300 mg for 26 to 36 kg; 400 mg for 37 to 50 kg [16].

Excretion -Feces

• 1) Feces, 10% to 23% [15].• a) Following administration of gabapentin, 10% to 23% was excreted

in the feces [15].

Clearance • Apparent oral clearance is directly proportional to CrCl• Clearance in infants is highly variable; oral clearance (per kg) in

children <5 years of age is higher than in children ≥5 years of age

Monitoring- Therapeutic

• 1) Physical Findings• a) Epilepsy• 1) Reduction in seizure frequency is indicative of a therapeutic

response to gabapentin.• b) Postherpetic Neuralgia• 1) Relief of pain associated with postherpetic neuralgia is indicative

of a therapeutic response to gabapentin.

Monitoring- Toxic

• 1) Physical Findings• a) Closely monitor patients for the emergence or worsening of

depression, suicidality, and/or any unusual behavioral or mood changes (ie, anxiety, agitation, hostility, mania, and hypomania) [18][19]

TOXICOLOGY• Although gabapentin’s mechanism of action is unclear, its sedating

effects are likely secondary to its lipophilic configuration and structural similarity to the inhibitory neurotransmitter GABA. • EPIDEMIOLOGY: Gabapentin overdose is uncommon and

manifestations are usually not severe.

TOXICOLOGY-continue• MILD TO MODERATE TOXICITY: In mild to moderate overdose, patients

may present with sedation, ataxia, slurred speech, nystagmus, movement disorders, and gastrointestinal upset. • SEVERE TOXICITY: In more severe cases, patients may present with

mild hypotension and profound central nervous system depression requiring intubation. • ADVERSE EFFECTS: Following therapeutic use, sedation, ataxia,

dizziness, fatigue, nystagmus, hypotension and hypertension have occurred. Leukopenia has also been described with therapeutic use. Rhabdomyolysis is a rare adverse effect.

REFERENCES• 1. Bril V, England J, Franklin GM, et al, "Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy: Report of the American Academy of Neurology, the

American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation," Neurology, 2011, 76(20):1758-65. [PubMed 21482920]

• 2. Butt DA, Lock M, Lewis JE, et al, “Gabapentin for the Treatment of Menopausal Hot Flashes: A Randomized Controlled Trial,” Menopause, 2008, 15(2):310-8. [PubMed 17917611]

• 3. Attal N, Cruccu G, Baron R, et al, "EFNS Guidelines on the Pharmacological Treatment of Neuropathic Pain: 2010 Revision," Eur J Neurol, 2010, 17(9):1113-e88. [PubMed 20402746]

• 4. Dworkin RH, O'Connor AB, Audette J, et al, "Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update," Mayo Clin Proc, 2010, 85(3 Suppl):3-14. [PubMed 20194146]

• 5. Barr J, Fraser G, Puntillo K, et al, “Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit,” Crit Care Med, 2013, 41(1):263-306. [PubMed23269131]

• 6. Doleman B, Heinink TP, Read DJ, Faleiro RJ, Lund JN, Williams JP. A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain. Anaesthesia. 2015;70(10):1186-1204. [PubMed 26300519]

• 7. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain control - a meta-analysis. Pain Res Manag. 2007;12(2):85-92. [PubMed 17505569]

• 8. Yu L, Ran B, Li M, Shi Z. Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery: a systematic review and meta-analysis. Spine (Phila Pa 1976). 2013;38(22):1947-1952. [PubMed 23921329]

REFERENCES• 9. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al, ”Treatment of Restless Legs Syndrome With Gabapentin: A Double-Blind, Cross-Over

Study,” Neurology, 2002, 59(10):1573-9. [PubMed 12451200]• 10. Happe S, Sauter C, Klosch G, et al, “Gabapentin Versus Ropinirole in the Treatment of Idiopathic Restless Legs

Syndrome,” Neuropsychobiology, 2003, 48(2):82-6. [PubMed 14504416]• 11. Saletu M, Anderer P, Saletu-Zyhlarz GM, et al, “Comparative Placebo-Controlled Polysomnographic and Psychometric Studies on the

Acute Effects of Gabapentin Versus Ropinirole in Restless Legs Syndrome,”J Neural Transm, 2010, 117(4):463-73. [PubMed 20049491]• 12. Vignatelli L, Billiard M, Clarenbach P, et al, “EFNS Guidelines on Management of Restless Leg Syndrome and Periodic Limb Movement

Disorder in Sleep,” Eur J Neurol, 2006, 13(10):1049-65.[PubMed 16987157]• 13. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin

Psychopharmacol. 1999;19(4):341-348. [PubMed 10440462]• 14 Sivenius J, Kalviainen R, Ylinen A, et al: Double-blind study of gabapentin in the treatment of partial seizures. Epilepsia 1991; 32:539-542.• 15 Vollmer KO, von Hodenberg A, & Kolle EU: Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittelforschung

1986; 36:830-839.• 16 Haig GM, Bockbrader HN, Wesche DL, et al: Single-dose gabapentin pharmacokinetics and safety in healthy infants and children. J Clin

Pharmacol 2001; 41:507-514.• 17 Anhut H, Leppik T, Schmidt B, et al: Drug interaction study of the new anticonvulsant gabapentin with phenytoin in epileptic patients

(abstract). Arch Pharmacol 1988; 337(Suppl.):R127.• 18 Product Information: Neurontin(R) oral capsules, tablets, solution, gabapentin oral capsules, tablets, solution. Parke-Davis, New York, NY,

2010.

REFERENCES• 19. Product Information: GRALISE(R) oral tablets, gabapentin oral tablets. Abbott Laboratories, North

Chicago, IL, 2011.

• 20. Meng FY, Zhang LC, Liu Y, et al: Efficacy and safety of gabapentin for treatment of postherpetic neuralgia: a meta-analysis of randomized controlled trials. Minerva Anestesiol 2014; 80(5):556-567.