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

Neuropsychiatric Disease and Treatment

Volumn 10, Issue , 2014, Pages 249-262

  Kume, Akito ^a,b  

^a Kume Clinic   (Japan)

^b Nagoya Clinical Neuropharmacology Laboratory   (Japan)

Author keywords

Dose finding; Gabapentin enacarbil; Meta analysis; Restless legs syndrome

Indexed keywords

GABAPENTIN ENACARBIL; PLACEBO;

CLINICAL TRIAL (TOPIC); DIZZINESS; DOSE CALCULATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG DOSE COMPARISON; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; HUMAN; INTERNATIONAL RESTLESS LEGS SYNDROME RATING SCALE; LOW DRUG DOSE; META ANALYSIS (TOPIC); PHARMACODYNAMICS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POLYSOMNOGRAPHY; QUALITY OF LIFE INDEX; RANDOMIZED CONTROLLED TRIAL (TOPIC); RATING SCALE; RESTLESS LEGS SYNDROME; REVIEW; RISK BENEFIT ANALYSIS; SEDATION; SLEEP DISORDER; SLEEP QUALITY; SOMNOLENCE; TREATMENT DURATION; TREATMENT OUTCOME;

EID: 84893600561     PISSN: 11766328     EISSN: 11782021     Source Type: Journal    
DOI: 10.2147/NDT.S30160     Document Type: Review

References (74)

1. Ekbom KA. Restless legs. Acta Med Scand. 1945;158(Suppl):1-123.
2. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J; Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4(2):101-119.
3. Tunç T, Karadaǧ YS, Doǧulu F, Inan LE. Predisposing factors of restless legs syndrome in pregnancy. Mov Disord. 2007;22(5):627-631.
4. Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord. 2007;22(Suppl 18):S440-S448.
5. Gigli GL, Adorati M, Dolso P, et al. Restless legs syndrome in end-stage renal disease. Sleep Med. 2004;5(3):309-315.
6. Gemignani F, Brindani F, Negrotti A, Vitetta F, Alfieri S, Marbini A. Restless legs syndrome and polyneuropathy. Mov Disord. 2006;21(8): 1254-1257.
7. Manconi M, Govoni V, De Vito A, etal. Restless legs syndrome and pregnancy. Neurology. 2004;63(6):1065-1069.
8. Allen RP, Walters AS, Montplaisir J, etal. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165(11):1286-1292.
9. Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, Ferini-Strambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5(3):237-246.
10. Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4): 283-295.
11. Innes KE, Selfe TK, Agarwal P. Prevalence of restless legs syndrome in North American and Western European populations: a systematic review. Sleep Med. 2011;12(7):623-634.
12. Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 2011;26(1):114-120.
13. Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: Prevalence and characteristics. Sleep Med. 2010;11(1): 31-37.
14. Nomura T, Inoue Y, Kusumi M, etal. Email-based epidemiological surveys on restless legs syndrome in Japan. Sleep Biol Rhythm. 2008;6: 139-145.
15. Nomura T, Inoue Y, Kusumi M, Uemura Y, Nakashima K. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord. 2008;23(16):2363-2369.
16. Mizuno S, Miyaoka T, Inagaki T, Horiguchi J. Prevalence of restless legs syndrome in non-institutionalized Japanese elderly. Psychiatry Clin Neurosci. 2005;59(4):461-465.
17. Garcia-Borreguero D, Kohnen R, Silber MH, etal. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(7):675-684.
18. Silber MH, Ehrenberg BL, Allen RP, etal; Medical Advisory Board of the Restless Legs Syndrome Foundation. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79(7): 916-922.
19. Oertel WH, Trenkwalder C, Zucconi M, etal. State of the art in restless legs syndrome therapy: practice recommendations for treating restless legs syndrome. Mov Disord. 2007;22(Suppl 18):S466-S475.
20. Trenkwalder C, Hening WA, Montagna P, etal. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord. 2008;23(16):2267-2302.
21. Hening WA. Current guidelines and standards of practice for restless legs syndrome. Am J Med. 2007;120(1 Suppl 1):S22-S27.
22. Vignatelli L, Billiard M, Clarenbach P, etal; EFNS Task Force. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. Eur J Neurol. 2006;13(10):1049-1065.
23. Bliwise DL, Freeman A, Ingram CD, Rye DB, Chakravorty S, Watts RL. Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome. Sleep Med. 2005;6(2):141-147.
24. Allen R, Becker PM, Bogan R, etal. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep. 2004;27(5):907-914.
25. Partinen M, Hirvonen K, Jama L, etal. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study-the PRELUDE study. Sleep Med. 2006;7(5):407-417.
26. García-Borreguero D, Allen RP, Benes H, etal. Augmentation as a treatment complication of restless legs syndrome: concept and management. Mov Disord. 2007;22(Suppl 18):S476-S484.
27. García-Borreguero D, Williams AM. Dopaminergic augmentation of restless legs syndrome. Sleep Med Rev. 2010;14(5):339-346.
28. Horizant® (gabapentin enacarbil) [prescribing information]. Santa Clara, CA: XenoPort, Inc.; revised May 2013.
29. Hendrich J, Van Minh AT, Heblich F, etal. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci U S A. 2008;105(9):3628-3633.
30. Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28(2):75-82.
31. Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, etal; European Federation of Neurological Societies; European Neurological Society; European Sleep Research Society. European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. Eur J Neurol. 2012;19(11):1385-1396.
32. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis. 2001;38(1):104-108.
33. Happe S, Sauter C, Klösch G, Saletu B, Zeitlhofer J. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology. 2003;48(2):82-86.
34. Micozkadioglu H, Ozdemir FN, Kut A, Sezer S, Saatci U, Haberal M. Gabapentin versus levodopa for the treatment of Restless Legs Syndrome in hemodialysis patients: an open-label study. Ren Fail. 2004;26(4):393-397.
35. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59(10):1573-1579.
36. Neurontin® (gabapentin) [prescribing information]. New York: Pfizer, Inc.; revised Dec 2012.
37. Gidal BE, Radulovic LL, Kruger S, Rutecki P, Pitterle M, Bockbrader HN. Inter-and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40(2-3):123-127.
38. Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res. 1993;10(2):276-281.
39. Lal R, Sukbuntherng J, Luo W, etal. Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers. Clin Ther. 2009;31(8):1776-1786.
40. XenoPort, Inc. Gabapentin Enacarbil (GSK1838262) Adult Restless Legs Syndrome Post Marketing commitment study (CONCORD). Available from: http://clinicaltrials.gov/ct2/show/NCT01668667?term=concord&rank=1. Accessed: January 6, 2014.
41. Lal R, Sukbuntherng J, Luo W, etal. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther. 2012;34(1):201-213.
42. Cundy KC, Sastry S, Luo W, Zou J, Moors TL, Canafax DM. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol. 2008;48(12):1378-1388.
43. Lal R, Ellenbogen A, Chen D, etal. A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome. Clin Neuropharmacol. 2012;35(4):165-173.
44. Cundy KC, Annamalai T, Bu L, etal. XP13512 [(±)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004;311(1):324-333.
45. Cundy KC, Branch R, Chernov-Rogan T, etal. XP13512 [(±)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004;311(1):315-323.
46. Lal R, Sukbuntherng J, Luo W, Huff FJ, Zou J, Cundy KC. The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil. Int J Clin Pharmacol Ther. 2010;48(2):120-128.
47. Lal R, Sukbuntherng J, Ho J, Cundy KC. A phase I, single-dose study of the disposition of 14C-radiolabeled gabapentin enacarbil in healthy male volunteers. Int J Clin Pharmacol Ther. 2011;49(2):109-115.
48. Lal R, Sukbuntherng J, Luo W, etal. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther. 2012;34(1):201-213.
49. Chen C. Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil. Eur J Clin Pharmacol. 2013;69(10):1809-1817.
50. Kushida CA, Walters AS, Becker P, etal; XP021 Study Group. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep. 2009;32(2):159-168.
51. Walters AS, Ondo WG, Kushida CA, etal; XP045 Study Group. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2009;32(6):311-320.
52. Kushida CA, Becker PM, Ellenbogen AL, Canafax DM, Barrett RW; XP052 Study Group. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology. 2009;72(5):439-446.
53. Lee DO, Ziman RB, Perkins AT, Poceta JS, Walters AS, Barrett RW; XP053 Study Group. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med. 2011;7(3): 282-292.
54. Bogan RK, Bornemann MA, Kushida CA, Trân PV, Barrett RW; XP060 Study Group. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010;85(6):512-521.
55. Ellenbogen AL, Thein SG, Winslow DH, etal. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol. 2011;34(1):8-16.
56. Winkelman JW, Bogan RK, Schmidt MH, Hudson JD, DeRossett SE, Hill-Zabala CE. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011;26(11):2065-2072.
57. VanMeter SA, Kavanagh ST, Warren S, Barrett RW. Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies. CNS Drugs. 2012;26(9):773-780.
58. Lal R, Sukbuntherng J, Luo W, Tovera J, Lassauzet ML, Cundy KC. Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil. J Clin Pharmacol. 2013;53(1):29-40.
59. Bogan RK, Ellenbogen A, Becker PM, etal. Gabapentin enacarbil in subjects with moderate to severe primary restless legs syndrome with and without severe sleep disturbance: an integrated analysis of subjective and novel sleep endpoints from two studies. J Parkinsonism Restless Legs Syndrome. 2013;3:31-40.
60. Inoue Y, Uchimura N, Kuroda K, Hirata K, Hattori N. Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(2):251-257.
61. Inoue Y, Hirata K, Uchimura N, Kuroda K, Hattori N, Takeuchi M. Gabapentin enacarbil in Japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin. 2013;29(1):13-21.
62. Center for Drug Evaluation and Research. Application number: 022399Orig1s000 Medical Review. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000MedR.pdf. Accessed: January 6, 2014.
63. Center for Drug Evaluation and Research. Application number: 022399Orig1s000 Summary Review. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000SumR.pdf. Accessed: January 6, 2014.
64. Irizarry MC, Webb DJ, Boudiaf N, etal. Risk of cancer in patients exposed to gabapentin in two electronic medical record systems. Pharmacoepidemiol Drug Saf. 2012;21(2):214-225.
65. Kohnen R, Allen RP, Benes H, etal. Assessment of restless legs syndrome-methodological approaches for use in practice and clinical trials. Mov Disord. 2007;22(Suppl 18):S485-S494.
66. Stiasny-Kolster K, Benes H, Peglau I, etal. Effective cabergoline treatment in idiopathic restless legs syndrome. Neurology. 2004;63(12): 2272-2279.
67. Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain. 2008;131(4):902-917.
68. Center for Drug Evaluation and Research. Application number: 022399Orig1s000 Pharmacology Review. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000PharmR.pdf. Accessed: January 6, 2014.
69. Center for Drug Evaluation and Research. Application number: 022399Orig1s000 Cross Discipline Team Leader Review. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000CrossR.pdf. Accessed: January 6, 2014.
70. Li Y, Walters AS, Chiuve SE, Rimm EB, Winkelman JW, Gao X. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation. 2012;126(14):1689-1694.
71. Innes KE, Selfe TK, Agarwal P. Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review. Sleep Med Rev. 2012;16(4):309-339.
72. Tippmann-Peikert M, Park JG, Boeve BF, Shepard JW, Silber MH. Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists. Neurology. 2007;68(4):301-303.
73. Driver-Dunckley ED, Noble BN, Hentz JG, etal. Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome. Clin Neuropharmacol. 2007;30(5):249-255.
74. Voon V, Schoerling A, Wenzel S, etal. Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome. BMC Neurol. 2011;11:117.