1) Shan H. Siddiqi, M.D., Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
2) Natalia K. Abraham, M.D., School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada.
3) Christopher L. Geiger, M.D., Department of Internal Medicine, University of Washington, Seattle, Washington, USA.
4) Morvarid Karimi, M.D., Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
5) Joel S. Perlmutter, M.D., Departments of Neurology, Radiology, and Anatomy & Neurobiology, Division of Biology and Biomedical Sciences, and Programs in Occupational Therapy and Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, USA.
6) Kevin J. Black, M.D., Departments of Psychiatry, Neurology, Radiology, and Anatomy & Neurobiology, and Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. ORCID 0000-0002-6921-9567
Address correspondence to Dr. Black at Campus Box 8134, 660 S. Euclid Ave., St. Louis, Missouri, USA, or kevin@WUSTL.edu.
Copyright © 2015, the authors.
NOTE: This was an early draft of an article whose final published version now appears as:
Siddiqi SH, Abraham NK, Geiger CL, Karimi M, Perlmutter JS and Black KJ (2016) The Human Experience with Intravenous Levodopa. Front. Pharmacol. 6:307. doi: 10.3389/fphar.2015.00307
Objective: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies.
Background: While safe intravenous use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data.
Methods: Over 200 articles referring to intravenous levodopa (IVLD) were examined for details of administration, pharmacokinetics, benefit and side effects.
Results: We identified 144 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. At least 2781 subjects have received IVLD, and reported outcomes include parkinsonian signs, sleep variables, hormones, hemodynamics, CSF amino acid composition, regional cerebral blood ﬂow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis.
Conclusion: At least 2781 patients have received i.v. levodopa with a safety profile comparable to that seen with oral administration.
Parkinson disease (PD), the second most common neurodegenerative disease, is associated with impairments in dopaminergic neurotransmission in the basal ganglia. Replacement of dopamine has been the cornerstone of treatment for PD. Because dopamine does not cross the blood-brain barrier (BBB), its immediate precursor levodopa (L-3,4-dihydroxphenylalanine, L-DOPA) is administered since it crosses the BBB (Birkmayer 2001, Hornykiewicz 1963, Cotzias 1967). Although purified levodopa was first ingested by mouth in 1913 (Roe 1997), when levodopa was first used for medical treatment in the late 1950s, it was given by the intravenous rather than the oral route (Pare 1959, Birkmayer 2001).
Oral levodopa has become the preferred method of treatment clinically, but intravenous levodopa administration still holds advantages over the oral form for some research studies. First, the rapid administration of intravenous levodopa is often necessary for certain study designs, including those focused on pharmacokinetics. Additionally, intravenous administration leads to more predictable plasma levodopa concentrations because oral medications have highly variable absorption characteristics, especially in PD patients (Bushmann 1989), with differences in absorption based on sex and age (Robertson 1989, Kompoliti 2002). Intravenous levodopa permits researchers to keep brain levodopa concentrations constant while assessing physiological responses over time. Furthermore, intravenous levodopa has sometimes been used clinically in patients who cannot tolerate oral medications, such as PD patients during surgery or on total parenteral nutrition.
Current U.S. FDA regulations focus heightened scrutiny to ensure safety of research studies with drugs delivered by a route for which the drug has not been approved. This heightened scrutiny, however, created practical obstacles to research with intravenous levodopa, as described for instance by Rascol and colleagues (p. 250 Rascol 2001). Specifically, an IND (Investigational New Drug) application must be submitted if risks of intravenous levodopa are significantly higher than those of oral levodopa (§21 CFR 312.2(b)(iii)). An IND application must include a comprehensive review of preclinical and human pharmacology. Therefore, the overall goal of this paper is to facilitate research use of IV levodopa by compiling a literature review that comprehensively summarizes the human experience with intravenously administered levodopa. We tabulate the extent of human exposure, side effects, benefits, and efficacy. We also summarize pharmacokinetic (PK) and pharmacodynamic parameters from these studies.