Skip to main content
SpringerLink
Log in

Novel Levodopa Formulations for Parkinson’s Disease

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Levodopa remains the most effective treatment for Parkinson’s disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa–carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa–carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the ‘accordion pill’ (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hornykiewicz O. A brief history of levodopa. J Neurol. 2010;257:S249–52.

    Article  PubMed  Google Scholar 

  2. Contin M, Martinelli P. Pharmacokinetics of levodopa. J Neurol. 2010;257:S253–61.

    Article  PubMed  Google Scholar 

  3. Seeberger LC, Hauser RA. Carbidopa levodopa enteral suspension. Expert Opin Pharmacother. 2015;16:2807–17.

    Article  CAS  PubMed  Google Scholar 

  4. Widnell K. Pathophysiology of motor fluctuations in Parkinson’s disease. Mov Disord. 2005;20(Suppl 11):S17–22.

    Article  PubMed  Google Scholar 

  5. Hutton JT, Morris JL. Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations. Can J Neurol Sci. 1991;18:467–71.

    Article  CAS  PubMed  Google Scholar 

  6. Yeh KC, August TF, Bush DF, Titus DC. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology. 1989;39:25–38.

    Article  CAS  PubMed  Google Scholar 

  7. Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol. 2013;12:346–56.

    Article  CAS  PubMed  Google Scholar 

  8. Pahwa R, Lyons KE, Hauser RA, Fahn S, Jankovic J, Pourcher E, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:142–8.

    Article  PubMed  Google Scholar 

  9. Hauser RA, Ellenbogen AL, Metman LV, Hsu A, O’Connell MJ, Modi NB, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Mov Disord. 2011;26:2246–52.

    Article  PubMed  Google Scholar 

  10. Mao Z, Hsu A, Gupta S, Modi NB. Population pharmacodynamics of IPX066: an oral extended-release capsule formulation of carbidopa-levodopa, and immediate-release carbidopa-levodopa in patients with advanced Parkinson’s disease. J Clin Pharmacol. 2013;53:523–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hsu A, Yao H-M, Gupta S, Modi NB. Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet® CR), and carbidopa-levodopa-entacapone (Stalevo®). J Clin Pharmacol. 2015;55:995–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yao H-M, Hsu A, Gupta S, Modi NB. Clinical pharmacokinetics of IPX066: evaluation of dose proportionality and effect of food in healthy volunteers. Clin Neuropharmacol. 2016;39:10–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stocchi F, Hsu A, Khanna S, Ellenbogen A, Mahler A, Liang G, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord. 2014;20:1335–40.

    Article  PubMed  Google Scholar 

  14. Nausieda PA, Hsu A, Elmer L, Gil RA, Spiegel J, Singer C, et al. Conversion to IPX066 from standard levodopa formulations in advanced Parkinson’s disease: experience in clinical trials. J Parkinsons Dis. 2015;5:837–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Greig SL, McKeage K. Carbidopa/levodopa ER capsules (Rytary®, Numient™): a review in Parkinson’s disease. CNS Drugs. 2016;30:79–90.

    Article  CAS  PubMed  Google Scholar 

  16. Waters CH, Nausieda P, Dzyak L, Spiegel J, Rudzinska M, Silver DE, et al. Long-term treatment with extended-release carbidopa-levodopa (IPX066) in early and advanced Parkinson’s disease: a 9-month open-label extension trial. CNS Drugs. 2015;29:341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. LeWitt PA, Friedman H, Giladi N. Accordion pill carbidopa/levodopa for improved treatment of advanced Parkinson’s disease symptoms [abstract]. Mov Disord. 2012;27(Suppl. 1):S408.

    Google Scholar 

  18. LeWitt P, Friedman H, Giladi N. Sustained-release carbidopa-levodopa (accordian pill) in patients with advanced Parkinson’s disease: pharmacokinetic and clinical experience [abstract]. Mov Disord. 2013;28(Suppl. 1):S499.

    Google Scholar 

  19. LeWitt PA, Giladi N, Gurevich T. Accordion pill carbidopa/levodopa (AP-CD/LD) for treatment of advanced Parkinson’s disease (PD) [abstract]. Mov Disord. 2014;29(Suppl. 1):S668.

    Google Scholar 

  20. Hou SYE, Cowles VE, Berner B. Gastric retentive dosage forms: a review. Crit Rev Ther Drug Carrier Syst. 2003;20:459–97.

    Article  PubMed  Google Scholar 

  21. Waterman KC. A critical review of gastric retentive controlled drug delivery. Pharm Dev Technol. 2007;12:1–10.

    Article  CAS  PubMed  Google Scholar 

  22. Prinderre P, Sauzet C, Fuxen C. Advances in gastro retentive drug-delivery systems. Expert Opin Drug Deliv. 2011;8:1189–203.

    Article  CAS  PubMed  Google Scholar 

  23. Chen C, Cowles VE, Sweeney M, Stolyarov ID, Illarioshkin SN. Pharmacokinetics and pharmacodynamics of gastroretentive delivery of levodopa/carbidopa in patients with Parkinson disease. Clin Neuropharmacol. 2012;35:67–72.

    Article  CAS  PubMed  Google Scholar 

  24. Verhagen Metman L, Stover N, Chen C, Cowles VE, Sweeney M. Gastroretentive carbidopa/levodopa, DM-1992, for the treatment of advanced Parkinson’s disease. Mov Disord. 2015;30:1222–8.

    Article  CAS  PubMed  Google Scholar 

  25. Chen C, Cowles VE, Sweeney M, Stolyarov ID, Illarioshkin SN. Pharmacokinetics of levodopa/carbidopa delivered from gastric-retentive extended-release formulations in patients with Parkinson’s disease. J Clin Pharmacol. 2012;52:1069–77.

    Article  CAS  PubMed  Google Scholar 

  26. Lewitt PA, Ellenbogen A, Chen D, Lal R, McGuire K, Zomorodi K, et al. Actively transported levodopa prodrug XP21279. Clin Neuropharmacol. 2012;35:103–10.

    Article  CAS  PubMed  Google Scholar 

  27. Lewitt PA, Huff FJ, Hauser RA, Chen D, Lissin D, Zomorodi K, et al. Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson’s disease. Mov Disord. 2014;29:75–82.

    Article  CAS  PubMed  Google Scholar 

  28. Muller T, Kuoppamaki M, Vahteristio M, Aho V. Novel levodopa product ODM-101 vs levodopa/carbidopa/entacapone in Parkinson’s disease with response fluctuations. Mov Disord. 2013;28:S146.

    Article  Google Scholar 

  29. Nyholm D, Nilsson Remahl AIM, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64:216–23.

    Article  CAS  PubMed  Google Scholar 

  30. Wirdefeldt K, Odin P, Nyholm D. Levodopa-carbidopa intestinal gel in patients with Parkinson’s disease: a systematic review. CNS Drugs. 2016;30:1–24.

    Article  Google Scholar 

  31. Othman AA, Dutta S. Population pharmacokinetics of levodopa in subjects with advanced Parkinson’s disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets. Br J Clin Pharmacol. 2014;78:94–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nyholm D, Odin P, Johansson A, Chatamra K, Locke C, Dutta S, et al. Pharmacokinetics of levodopa, carbidopa, and 3-O-methyldopa following 16-hour jejunal infusion of levodopa-carbidopa intestinal gel in advanced Parkinson’s disease patients. AAPS J. 2013;15:316–23.

    Article  CAS  PubMed  Google Scholar 

  33. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13:141–9.

    Article  CAS  PubMed  Google Scholar 

  34. Fernandez HH, Vanagunas A, Odin P, Espay AJ, Hauser RA, Standaert DG, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease open-label study: interim results. Parkinsonism Relat Disord. 2013;19:339–45.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Antonini A, Yegin A, Preda C, Bergmann L, Poewe W, GLORIA study investigators and coordinators. Global long-term study on motor and non-motor symptoms and safety of levodopa-carbidopa intestinal gel in routine care of advanced Parkinson’s disease patients; 12-month interim outcomes. Parkinsonism Relat Disord. 2015;21:231–5.

    Article  PubMed  Google Scholar 

  36. Zibetti M, Merola A, Ricchi V, Marchisio A, Artusi CA, Rizzi L, et al. Long-term duodenal levodopa infusion in Parkinson’s disease: a 3-year motor and cognitive follow-up study. J Neurol. 2013;260:105–14.

    Article  CAS  PubMed  Google Scholar 

  37. Zibetti M, Merola A, Artusi CA, Rizzi L, Angrisano S, Reggio D, et al. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson’s disease: a 7-year experience. Eur J Neurol. 2014;21:312–8.

    Article  CAS  PubMed  Google Scholar 

  38. Fernandez HH, Standaert DG, Hauser RA, Lang AE, Fung VSC, Klostermann F, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease: final 12-month, open-label results. Mov Disord. 2015;30:500–9.

    Article  CAS  PubMed  Google Scholar 

  39. Galazky I, Schoof J, Stallforth S, Kupsch A, Heinze H-J, Kluge C. Guillain–Barre/CIDP-like neuropathy in two parkinsonian patients following intestinal levodopa/carbidopa treatment. Parkinsonism Relat Disord. 2014;20:125–7.

    Article  PubMed  Google Scholar 

  40. Manca D, Cossu G, Murgia D, Molari A. Reversible encephalopathy and axonal neuropathy in Parkinson’s disease during duodopa therapy. Mov Disord. 2009;24:2289–308.

    Article  Google Scholar 

  41. Urban PP, Wellach I, Faiss S, Layer P. Subacute axonal neuropathy in Parkinson’s disease with cobalamin and vitamin B6 deficiency under duodopa therapy. Mov Disord. 2010;25:1744–52.

    Article  Google Scholar 

  42. Lehnerer SM, Fietzek UM, Messner M, Ceballos-Baumann AO. Subacute peripheral neuropathy under duodopa therapy without cobalamin deficiency and despite supplementation. J Neural Transm. 2014;121:1269–72.

    Article  CAS  PubMed  Google Scholar 

  43. Mancini F, Comi C, Oggioni GD, Pacchetti C, Calandrella D, Coletti Moja M, et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens. Parkinsonism Relat Disord. 2014;20:27–31.

    Article  CAS  PubMed  Google Scholar 

  44. Jugel C, Ehlen F, Taskin B, Marzinzik F, Müller T, Klostermann F. Neuropathy in Parkinson’s disease patients with intestinal levodopa infusion versus oral drugs. PLoS One. 2013;8:e66639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Uncini A, Eleopra R, Onofrj M. Polyneuropathy associated with duodenal infusion of levodopa in Parkinson’s disease: features, pathogenesis and management. J Neurol Neurosurg Psychiatr. 2015;86:490–5.

    Article  PubMed  Google Scholar 

  46. Caraco Y, Oren S, LeWitt P. Constant therapeutic levodopa (LD) plasma concentrations maintained by continuous subcutaneous (SC) administration of ND-0612, a novel formulation of LD/carbidopa (CD) [abstract]. Mov Disord. 2013;28(Suppl. 1):S452.

    Google Scholar 

  47. Giladi N, Caraco Y, Gurevich T, Djaldetti R. Pharmacokinetics and safety of ND0612L (levodopa/carbidopa for subcutaneous infusion): results from a phase II study in moderate to severe Parkinson’s disease [abstract]. Neurology. 2015;84(Suppl. P1):187.

  48. Giladi N, Caraco Y, Gurevich T, Djaldetti R, Olanow CW. Stable levodopa plasma levels with ND0612 (levodopa/carbidopa for subcutaneous infusion) in Parkinson’s disease (PD) patients with motor fluctuations [abstract]. Mov Disord. 2015;30:1995.

    Google Scholar 

  49. Giladi N, Caraco Y, Gurevich T. Pharmacokinetic profile of ND0612L (levodopa/carbidopa for subcutaneous infusion) in patients with moderate to severe Parkinson’s disease [abstract]. Mov Disord 2015;30(Suppl. 1):S226.

  50. Luinstra M, Grasmeijer F, Hagedoorn P, Moes JR, Frijlink HW, de Boer AH. A levodopa dry powder inhaler for the treatment of Parkinson’s disease patients in off periods. Eur J Pharm Biopharm. 2015;97:22–9.

    Article  CAS  PubMed  Google Scholar 

  51. Lewitt PA, Hauser RA, Grosset DG, Stocchi F, Saint-Hilaire M-H, Ellenbogen A, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31:1356–65.

    Article  CAS  PubMed  Google Scholar 

  52. Dhall R, Kreitzman DL. Advances in levodopa therapy for Parkinson disease: review of RYTARY (carbidopa and levodopa) clinical efficacy and safety. Neurology. 2016;86:S13–24.

    Article  CAS  PubMed  Google Scholar 

  53. Dewey RB, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for Parkinsonian off-state events. Arch Neurol. 2001;58:1385–92.

    Article  PubMed  Google Scholar 

  54. Trosch RM, Silver D, Bottini PB. Intermittent subcutaneous apomorphine therapy for ‘off’ episodes in Parkinson’s disease: a 6-month open-label study. CNS Drugs. 2008;22:519–27.

    Article  CAS  PubMed  Google Scholar 

  55. Merello M, Pikielny R, Cammarota A, Leiguarda R. Comparison of subcutaneous apomorphine versus dispersible madopar latency and effect duration in Parkinson’s disease patients: a double-blind single-dose study. Clin Neuropharmacol. 1997;20:165–7.

    Article  CAS  PubMed  Google Scholar 

  56. Blindauer K, Shoulson I, Oakes D, Kieburtz K, Schwid S, Fahn S, et al. A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations. Arch Neurol. 2006;63:210–6.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Movement Disorders Centre and Edmond J. Safra Program in Parkinson’s Disease, Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst Street MCL7-412, Toronto, ON, M5T 2S8, Canada

    Maria Eliza Freitas, Marta Ruiz-Lopez & Susan H. Fox

Authors
  1. Maria Eliza Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Ruiz-Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan H. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan H. Fox.

Ethics declarations

Funding

No funding was specifically received for the publication of this article.

Conflict of interest

Susan Fox has received consultancy fees from Adamas, Astra Zeneca, Kyowa, Teva, Novartis, Orion, and Zambon and speaker honoraria from the International Parkinson and Movement Disorder Society and American Academy of Neurology. Maria Eliza Freitas and Marta Ruiz-Lopez have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Freitas, M.E., Ruiz-Lopez, M. & Fox, S.H. Novel Levodopa Formulations for Parkinson’s Disease. CNS Drugs 30, 1079–1095 (2016). https://doi.org/10.1007/s40263-016-0386-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-016-0386-8

Keywords

Search

Navigation