A comprehensive update on the ADMET considerations for α2δ calcium channel ligand medications for treating restless legs syndrome

References

• American Academy of Sleep Medicine. In: Sateia M, editor. International Classification of Sleep Disorders. 3rd ed, text revision. Darien (IL): American Academy of Sleep Medicine; 2023. p. 346–355.
   Google Scholar
• Manconi M, Garcia-Borreguero D, Schormair B, et al. Restless legs syndrome. Nat Rev Dis Primers. 2021;7(1):80. doi: 10.1038/s41572-021-00311-z
   PubMedGoogle Scholar
• Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis–ekbom disease diagnostic criteria: updated international restless legs syndrome study group (IRLSSG) consensus criteria – history, rationale, description, and significance. Sleep Med. 2014;15(8):860–873. doi: 10.1016/j.sleep.2014.03.025
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Lavigne GJ, Montplaisir JY Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17:739–743. 8
   PubMed Web of Science ®Google Scholar
• Juuti AK, Läärä E, Rajala U, et al. Prevalence and associated factors of restless legs in a 57-year-old urban population in northern Finland: prevalence of RLS. Acta Neurol Scand. 2009;122(1):63–69. doi: 10.1111/j.1600-0404.2009.01262.x
   PubMed Web of Science ®Google Scholar
• Whittom S, Dauvilliers Y, Pennestri M-H, et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med. 2007;9(1):54–59. doi: 10.1016/j.sleep.2007.01.017
   PubMed Web of Science ®Google Scholar
• Yeh P, Walters AS, Tsuang JW. Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath. 2012;16(4):987–1007. doi: 10.1007/s11325-011-0606-x
   PubMed Web of Science ®Google Scholar
• Picchietti DL, Hensley JG, Bainbridge JL, et al. Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-ekbom disease during pregnancy and lactation. Sleep Med Rev. 2015;22:64–77. doi: 10.1016/j.smrv.2014.10.009
   PubMed Web of Science ®Google Scholar
• Srivanitchapoom P, Pandey S, Hallett M. Restless legs syndrome and pregnancy: a review. Parkinsonism Relat Disord. 2014;20(7):716–722. doi: 10.1016/j.parkreldis.2014.03.027
   PubMed Web of Science ®Google Scholar
• Merlino G, Lorenzut S, Gigli GL, et al. A case‐control study on restless legs syndrome in nondialyzed patients with chronic renal failure. Mov Disord. 2010;25(8):1019–1025. doi: 10.1002/mds.23010
   PubMed Web of Science ®Google Scholar
• Merlino G, Lorenzut S, Romano G, et al. Restless legs syndrome in dialysis patients: a comparison between hemodialysis and continuous ambulatory peritoneal dialysis. Neurol Sci. 2012;33(6):1311–1318. doi: 10.1007/s10072-012-0953-9
   PubMed Web of Science ®Google Scholar
• Italian REMS Study Group T, Manconi M, Ferini-Strambi L, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep. 2008;31:944–952. 7 10.5665/sleep/31.7.944
   PubMed Web of Science ®Google Scholar
• Merlino G, Fratticci L, Valente M, et al. Association of restless legs syndrome in type 2 diabetes: a case-control study. Sleep. 2007;30(7):866–871. doi: 10.1093/sleep/30.7.866
   PubMed Web of Science ®Google Scholar
• Gigli GL, De Biase S, Pellitteri G, et al. Restless legs syndrome in internal medicine. In: Kushida C, editor. Encyclopedia of sleep and circadian rhythms. Cambridge (MA): Elsevier; 2023. p. 743–756.
   Google Scholar
• Trenkwalder C, Allen R, Högl B, et al. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology. 2016;86(14):1336–1343. doi: 10.1212/WNL.0000000000002542
   PubMed Web of Science ®Google Scholar
• Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, et al. Genetics of restless legs syndrome: an update. Sleep Med Rev. 2018;39:108–121. doi: 10.1016/j.smrv.2017.08.002
   PubMed Web of Science ®Google Scholar
• Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord. 2007;22(S18):S440–S448. doi: 10.1002/mds.21607
   PubMedGoogle Scholar
• O’Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23(3):200–203. doi: 10.1093/ageing/23.3.200
   PubMed Web of Science ®Google Scholar
• Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27–44. doi: 10.1016/j.sleep.2017.11.1126
   PubMed Web of Science ®Google Scholar
• Merlino G, Dolso P, Canesin R, et al. The acute effect of a low dosage of pramipexole on severe idiopathic restless legs syndrome: an open-label trial. Neuropsychobiology. 2006;54(3):195–200. doi: 10.1159/000099947
   PubMed Web of Science ®Google Scholar
• Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004;5(4):385–391. doi: 10.1016/j.sleep.2004.01.012
   PubMed Web of Science ®Google Scholar
• Eisensehr I, Wetter TC, Linke R, et al. Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome. Neurology. 2001;57(7):1307–1309. doi: 10.1212/WNL.57.7.1307
   PubMed Web of Science ®Google Scholar
• Trenkwalder C, Walters AS, Hening WA, et al. Positron emission tomographic studies in restless legs syndrome. Mov Disord. 1999;14(1):141–145. doi: 10.1002/1531-8257(199901)14:1<141:AID-MDS1024>3.0.CO;2-B
   PubMed Web of Science ®Google Scholar
• Erikson KM, Jones BC, Hess EJ, et al. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001;69(3–4):409–418. doi: 10.1016/S0091-3057(01)00563-9
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, et al. 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. doi: 10.1111/j.1468-1331.2012.03853.x
   PubMed Web of Science ®Google Scholar
• Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585–2593. doi: 10.1212/WNL.0000000000003388
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis–ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11. doi: 10.1016/j.sleep.2016.01.017
   PubMed Web of Science ®Google Scholar
• Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921–1937. doi: 10.1016/j.mayocp.2020.12.026
   PubMed Web of Science ®Google Scholar
• Chertow GM, Mason PD, Vaage-Nilsen O, et al. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004;19(6):1571–1575. doi: 10.1093/ndt/gfh185
   PubMed Web of Science ®Google Scholar
• De Biase S, Pellitteri G, Gigli GL, et al. Advancing synthetic therapies for the treatment of restless legs syndrome. Expert Opin Pharmacother. 2019;20(16):1971–1980. doi: 10.1080/14656566.2019.1654997
   PubMed Web of Science ®Google Scholar
• De Biase S, Merlino G, Lorenzut S, et al. ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome. Expert Opin Drug Metab Toxicol. 2014;10(10):1365–1380. doi: 10.1517/17425255.2014.952629
   PubMed Web of Science ®Google Scholar
• García-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine–International Restless Legs Syndrome Study Group consensus conference at the max Planck institute. Sleep Med. 2007;8(5):520–530. doi: 10.1016/j.sleep.2007.03.022
   PubMed Web of Science ®Google Scholar
• Allen RP, Ondo WG, Ball E, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med. 2011;12(5):431–439. doi: 10.1016/j.sleep.2011.03.003
   PubMed Web of Science ®Google Scholar
• Trenkwalder C, Winkelmann J, Inoue Y, et al. Restless legs syndrome—current therapies and management of augmentation. Nat Rev Neurol. 2015;11(8):434–445. doi: 10.1038/nrneurol.2015.122
   PubMed Web of Science ®Google Scholar
• Field MJ, Li Z, Schwarz JB. Ca 2+ channel α 2 -δ ligands for the treatment of neuropathic pain. J Med Chem. 2007;50(11):2569–2575. doi: 10.1021/jm060650z
   PubMed Web of Science ®Google Scholar
• Chincholkar M. Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain. 2020;14(2):104–114. doi: 10.1177/2049463720912496
   PubMed Web of Science ®Google Scholar
• Lal R, Sukbuntherng J, Luo W, et al. Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil. J Clin Pharmacol. 2013;53(1):29–40. doi: 10.1177/0091270012439209
   PubMed Web of Science ®Google Scholar
• Kim J-Y, Abdi S, Huh B, et al. Mirogabalin: could it be the next generation gabapentin or pregabalin? Korean J Pain. 2021;34(1):4–18. doi: 10.3344/kjp.2021.34.1.4
   PubMed Web of Science ®Google Scholar
• Chincholkar M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br J Anaesth. 2018;120(6):1315–1334.
   PubMed Web of Science ®Google Scholar
• Garbazza C, Manconi M. Management strategies for restless legs syndrome/Willis-ekbom disease during pregnancy. Sleep Med Clin. 2018;13(3):335–348. doi: 10.1016/j.jsmc.2018.05.001
   PubMedGoogle Scholar
• Faulkner MA. Use of α2δ ligands for restless legs syndrome/Willis ekbom disease. CNS Drugs. 2018;32(2):149–159. doi: 10.1007/s40263-018-0502-z
   PubMed Web of Science ®Google Scholar
• 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):1573–1579. doi: 10.1212/WNL.59.10.1573
   PubMed Web of Science ®Google Scholar
• 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):463–473. doi: 10.1007/s00702-009-0361-3
   PubMed Web of Science ®Google Scholar
• Happe S, Sauter C, Klösch G, et al. Gabapentin versus Ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology. 2003;48(2):82–86. doi: 10.1159/000072882
   PubMed Web of Science ®Google Scholar
• Ghadami M, Razazian N, Azimi H, et al. Gabapentin versus levodopa-c for the treatment of restless legs syndrome in hemodialysis patients: a randomized clinical trial. Saudi J Kidney Dis Transpl. 2015;26(2):271. doi: 10.4103/1319-2442.152417
   PubMedGoogle Scholar
• Davison SN. Clinical pharmacology considerations in pain management in patients with advanced kidney failure. CJASN. 2019;14(6):917–931. doi: 10.2215/CJN.05180418
   PubMed Web of Science ®Google Scholar
• Gabapentin (neurontin), prescribing information. [cited 2024 Jan 11]. Available from: https://www.Ema.europa.eu/en/medicines/human/referrals/neurontin
   Google Scholar
• Gidal BE, Maly MM, Kowalski JW, et al. Gabapentin absorption: effect of mixing with foods of varying macronutrient composition. Ann Pharmacother. 1998;32(4):405–409. doi: 10.1345/aph.17281
   PubMed Web of Science ®Google Scholar
• Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of Pregabalin and Gabapentin. Clinical Pharmacokinet. 2010;49(10):661–669. doi: 10.2165/11536200-000000000-00000
   PubMed Web of Science ®Google Scholar
• Gidal BE, Radulovic LL, Kruger S, et al. Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40(2–3):123–127. doi: 10.1016/S0920-1211(00)00117-0
   PubMed Web of Science ®Google Scholar
• Beydoun A, Uthman BM, Sackellares JC. Gabapentin: pharmacokinetics, efficacy, and safety. Clin Neuropharmacol. 1995;18(6):469–481. doi: 10.1097/00002826-199512000-00001
   PubMed Web of Science ®Google Scholar
• Vollmer KO, von Hodenberg A, Kölle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittelforschung. 1986;36(5):830–839.
   PubMed Web of Science ®Google Scholar
• Rose MA, Kam PCA. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57(5):451–462. doi: 10.1046/j.0003-2409.2001.02399.x
   PubMed Web of Science ®Google Scholar
• Ahmed M, Hays R, Steven Poceta J, et al. Effect of gabapentin enacarbil on individual items of the international restless legs study group rating scale and Post-sleep Questionnaire in adults with moderate-to-severe primary restless legs syndrome: pooled analysis of 3 randomized trials. Clin Ther. 2016;38(7):1726–1737.e1. doi: 10.1016/j.clinthera.2016.05.008
   PubMed Web of Science ®Google Scholar
• Lee DO, Ziman RB, Perkins AT, et al. 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. doi: 10.5664/JCSM.1074
   PubMed Web of Science ®Google Scholar
• Ellenbogen AL, Thein SG, Winslow DH, et al. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol. 2011;34(1):8–16. doi: 10.1097/WNF.0b013e3182087d48
   PubMed Web of Science ®Google Scholar
• Winkelman JW, Bogan RK, Schmidt MH, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011;26(11):2065–2072. doi: 10.1002/mds.23771
   PubMed Web of Science ®Google Scholar
• Iftikhar IH, Alghothani L, Trotti LM. Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta‐analysis. Eur J Neurol. 2017;24(12):1446–1456. doi: 10.1111/ene.13449
   PubMed Web of Science ®Google Scholar
• Yaltho TC, Ondo WG. The use of gabapentin enacarbil in the treatment of restless legs syndrome. Ther Adv Neurol Disord. 2010;3(5):269–275. doi: 10.1177/1756285610378059
   PubMedGoogle Scholar
• Hayes WJ, Lemon MD, Farver DK. Gabapentin enacarbil for treatment of restless legs syndrome in adults. Ann Pharmacother. 2012;46(2):229–239. doi: 10.1345/aph.1Q578
   PubMed Web of Science ®Google Scholar
• Calandre EP, Rico-Villademoros F, Slim M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother. 2016;16(11):1263–1277. doi: 10.1080/14737175.2016.1202764
   PubMed Web of Science ®Google Scholar
• Farquhar-Smith P, Thomas. Gabapentin enacarbil extended release for the treatment of postherpetic neuralgia in adults. TCRM. 2013;469.10.2147/TCRM.S50212
   Google Scholar
• Kim ES, Deeks ED. Gabapentin Enacarbil: A Review in Restless Legs Syndrome. Drugs. 2016;76(8):879–887. doi: 10.1007/s40265-016-0584-1
   PubMed Web of Science ®Google Scholar
• Gabapentin enacarbil (HORIZANT), prescribing information [cited 2024 Jan 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022399s011lbl.pdf
   Google Scholar
• Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512–519. doi: 10.1016/j.sleep.2010.03.003
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Larrosa O, Williams A-M, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology. 2010;74(23):1897–1904. doi: 10.1212/WNL.0b013e3181e1ce73
   PubMed Web of Science ®Google Scholar
• Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370(7):621–631. doi: 10.1056/NEJMoa1303646
   PubMed Web of Science ®Google Scholar
• Bae H, Cho YW, Kim KT, et al. The safety and efficacy of Pregabalin add-on therapy in restless legs syndrome patients. Front Neurol. 2021;12:786408. doi: 10.3389/fneur.2021.786408
   PubMed Web of Science ®Google Scholar
• Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43(3):277–283. doi: 10.1177/0091270003251119
   PubMed Web of Science ®Google Scholar
• Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol. 2010;50(8):941–950. doi: 10.1177/0091270009352087
   PubMed Web of Science ®Google Scholar
• Ben‐Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(s6):13–18. doi: 10.1111/j.0013-9580.2004.455003.x
   PubMed Web of Science ®Google Scholar
• Lockwood PA, Pauer L, Scavone JM, et al. The pharmacokinetics of pregabalin in breast milk, plasma, and urine of healthy postpartum women. J Hum Lact. 2016;32(3):NP1–NP8. doi: 10.1177/0890334415626148
   PubMed Web of Science ®Google Scholar
• Pregabalin (lyrica), prescribing information. [cited 2024 Jan 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/lyrica
   Google Scholar
• Baldini A, Von Korff M, Lin EH. A review of potential adverse effects of long-term opioid therapy: a practitioner’s guide. Prim Care Companion CNS Disord. 2012;14:PCC.11m01326. doi: 10.4088/PCC.11m01326
   PubMedGoogle Scholar
• Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome. Sleep. 2014;37(4):635–643. doi: 10.5665/sleep.3558
   PubMed Web of Science ®Google Scholar
• Oertel W, Trenkwalder C, Beneš H, et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. Lancet Neurol. 2011;10(8):710–720. doi: 10.1016/S1474-4422(11)70127-2
   PubMed Web of Science ®Google Scholar
• Silver N, Allen RP, Senerth J, et al. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12(5):440–444. doi: 10.1016/j.sleep.2010.11.002
   PubMed Web of Science ®Google Scholar
• Lipford MC, Silber MH. Long-term use of pramipexole in the management of restless legs syndrome. Sleep Med. 2012;13(10):1280–1285. doi: 10.1016/j.sleep.2012.08.004
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Cano-Pumarega I, Garcia Malo C, et al. Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment. Sleep Med. 2019;55:74–80. doi: 10.1016/j.sleep.2018.11.025
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Cano I, Granizo JJ. Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel. Sleep Med. 2017;34:105–108. doi: 10.1016/j.sleep.2017.03.012
   PubMed Web of Science ®Google Scholar
• Garcia-Borreguero D, Guitart X, Garcia Malo C, et al. Treatment of restless legs syndrome/Willis-ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med. 2018;45:94–97. doi: 10.1016/j.sleep.2018.02.002
   PubMed Web of Science ®Google Scholar
• Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome. Chest. 2009;135(1):74–80. doi: 10.1378/chest.08-1665
   PubMed Web of Science ®Google Scholar
• Heide AC, Winkler T, Helms HJ, et al. Effects of transcutaneous spinal direct Current stimulation in idiopathic restless legs patients. Brain Stimul. 2014;7(5):636–642. doi: 10.1016/j.brs.2014.06.008
   PubMed Web of Science ®Google Scholar