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{\LARGE
\textbf{The human experience with intravenous levodopa}
}
% Insert Author names, affiliations and corresponding author email.
\\

 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.  \href{http://orcid.org/0000-0002-6921-9567}{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 \copyright\, 2015, the authors.

\textbf{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

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\section{Introduction}
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 \cite{11763859,13954967,5334614}. Although purified levodopa was first ingested by mouth in 1913 \cite{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 \cite{14430381,11763859}.

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 \cite{2797454}, with differences in absorption based on sex and age \cite{2775615,12011296}.  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 \cite[p. 250]{11176963}.  Specifically, an IND (Investigational New Drug) application must be submitted if risks of intravenous levodopa are significantly higher than those of oral levodopa (\href{http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.2}{\S 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. 


\section{Methods}
The authors searched MEDLINE and OVID, reviewed selected books, searched toxicity databases, and followed references cited in those sources. Articles written completely in languages other than English, German, Italian, Spanish, or Portuguese were excluded. Search terms included (levodopa / L-dopa / DOPA) AND (intravenous / intravascular / infusion / injection / i.v.); limit to humans; search date through May, 2015. Information from studies using oral or intraduodenal L-DOPA administration was excluded except for PK/PD tables.  Studies in which IV levodopa was always coadministered with monoamine oxidase inhibitors (MAOIs) or catechol-O-methyltransferase (COMT) inhibitors were excluded.  Levodopa methyl ester \cite{3601092} and DL-dopa \cite{14430381} were included, but PK/PD calculations were corrected for the difference in molecular weights.  Co-administered drugs were reported if included by the authors.

We recorded total dose, maximum infusion rate, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters where available, including steady state volume of distribution (VOD), clearance, distribution half life ($t_{\frac{1}{2}\alpha}$), and elimination half life ($t_{\frac{1}{2}}$ or $t_{\frac{1}{2}\beta}$), $E_{max}$, and $EC_{50}$). Reported data were used to calculate any missing PK parameters where possible.  Additionally, any reports on efficacy were noted.  Side effect frequency was recorded if reported. The number of subjects and subject conditions (Parkinson disease, other disease states or healthy volunteers) were recorded for each study. 

Average PK parameters were calculated across studies, weighted by the number of subjects.
  

\section{Results}
139 articles reporting intravenous levodopa administration were identified.  Most subjects with parkinsonism were diagnosed with idiopathic PD, but some studies reported a variety of etiologies including postencephalitic and vascular parkinsonism and PSP.  PD patients differed in their history of prior drug treatment before the studies with conditions including de novo, fluctuating, on-off, and stable.  Some subjects were treated with levodopa for conditions other than PD (see Table 1: Patient Populations and Response Parameters), including other movement disorders (dystonia, progressive supranuclear palsy [PSP], neuroleptic malignant syndrome [NMS], primary psychiatric disorders (schizophrenia, mood disorders, personality disorders),  endocrine disorders (diabetes mellitus, essential obesity, hypopituitarism), hepatic disease (alcoholic cirrhosis, steatohepatitis, hepatic encephalopathy), cardiac valvular disease, and asthma.  Healthy controls were also included in some studies.

Pharmacokinetic data were reported for a total of 251 human subjects (see Table 2: Pharmacokinetics of IV Levodopa).  Co-administration of a peripheral decarboxylase inhibitor (PDI) lowered the clearance and elimination half-life of intravenously administered levodopa, while there was no notable effect of PDIs on volume of distribution.

The pharmacodynamic data (see Table 3: Reports of Human Experience with IV Levodopa) obtained from the literature  surveyed a total of 2781 human subjects, with a significant variety of patient groups studied and a multitude of response parameters (see Table 1).  From these articles, no side effects were reported for a total of 1260 subjects.  The highest total dose was 4320 mg in one day, given to a patient with idiopathic PD and carcinoma of the retina.  The patient reported no adverse effects at this dose.  The highest single bolus dose was 200 mg, while the highest steady infusion rate was 5 mg/kg/hr.

Concomitantly administered peripheral decarboxylase inhibitors included carbidopa and benserazide.  Often, PDIs affected clearance and volume of distribution (as mentioned above), minimized gastrointestinal symptoms, and allowed subjects to be given lower doses of levodopa.    

Othet concomitant drugs were also listed, to help explain any side effects that might be caused by concomitant drug administration rather than by levodopa alone.  These included adenosine receptor antagonists (istradefylline, tozadenant [SYN115] aminophylline, caffeine), stimulants (amphetamines, methylphenidate), dopamine receptor agonists (apomorphine, terguride, SKF38393), monoamine oxidase (MAO) inhibitors, dextromethorphan, estradiol, paroxetine, and dantrolene.  

A variety of neurological, psychiatric, cardiovascular, and other physiological effects of levodopa  were monitored (see Table 1). There were no reported deaths.  There were no instances of psychosis, even when attempting to elicit it in susceptible subjects \cite{9748031}.  There were also no life-threatening events (serious adverse effects) following intravenous levodopa administration at high doses, regardless of whether a PDI was co-administered.  With co-administration of a PDI, the dosage range causing side effects (mainly nausea and asymptomatic hypotension) was a 0.5-2.0 mg/kg/hr infusion or a 45-150 mg bolus.  Without a co-administered PDI, side effects were reported at a 1.5-3.0 mg/kg/hr infusion or a 60-200 mg bolus. It should be noted that occurrence of side effects was more likely with higher doses, but other factors such as age, sex, disease severity, and prior treatment also played a role in side effects of levodopa.  

Other than these side effects found at high doses, several milder or less frequent side effects were reported. These primarily included mild autonomic changes (orthostasis and tachycardia), psychiatric changes (sedation, anxiety, insomnia, and mood improvements), and neurologic effects (improvements in tics, REM sleep changes, subjective weakness, headaches, and increased dyskinesias). Various other effects were noted in isolated reports (table 3). It is important to note that both side effects and efficacy depended strongly on subject factors including gender, age, past treatment, and disease state.  Also, dsykinesia was mentioned as a side effect only in patients with PD, and most often in those with a long history of previous levodopa treatment. 

Motor benefits of levodopa in PD have been demonstrated conclusively. Additional reported benefits of intravenous levodopa treatment in PD included improved sleep \cite{6722513} and attenuation of early morning akinesia or dystonia \cite{3601092}.  In other patient groups, benefits of intravenous levodopa included improvement of the comatose state in hepatic encephalopathy \cite{4544184} and improvement in depressive and somatoform symptoms \cite{5898634}.  Some studies found it to be superior to other treatment options for neuroleptic malignant syndrome \cite{9099421}.  More recently, intravenous levodopa was found to alleviate neuropsychiatric adverse effects (lethargy, hypersomnia, depression, agitation, akathisia, and confusion) associated with interferon-alpha \cite{10682234}. All these effects are summarized in Table B.
  

\section{Discussion}
The existing literature strongly supports the safety of intravenous levodopa, which has been used in humans for more than half a century \cite{14430381}.  Intravenous levodopa has been administered to over 2600 human subjects.  Despite infusion rates as high as 5.0 mg/kg/hr and boluses as large as 200 mg, there are no recorded instances of death or of other serious adverse effects of intravenous levodopa, nor have there been documented cases of other serious side effects, such as psychosis, that might limit its use in humans. Milder side effects, the most significant of which are nausea and vomiting, were most prominent with rapid infusions in the range of 1-2 mg/kg or 100-200 mg over less than 15 minutes \cite{5327616,Bbrung_1966,12865145,4555619,6540399,4880674}. 

These conclusions are supported by safety data from other species. The registry of toxic effects of chemical substances (RTECS) reports the lowest published toxic dose of levodopa in any non-human species as 2.5 mg/kg, referring to a subtle behavioral effect on a learning measure in a mouse, while higher doses have not been reported to cause similar effects in humans.  The lowest intravenous levodopa dose that was lethal to half of subjects (LD50) was ``>100 mg/kg'' in rats.  In mice, the LD50 ranges from 450 mg/kg (administered intravenously) to 4449 mg/kg (administered subcutaneously) \cite{rtecs}.  Typical human i.v. doses are in the range of only 1 mg/kg; thus, human studies with intravenous levodopa administer doses substantially lower than those dangerous to nonhuman mammals. 

Intravenous levodopa has similar efficacy and side effects as oral levodopa \cite{Connolly_2014} and dopamine agonists \cite{Bonuccelli_2008}.  These include GI (nausea, vomiting, and abdominal discomfort) and neuropsychiatric effects (sedation, dyskinesias).  Nausea and orthostatic hypotension, side effects of both IV and oral levodopa, are largely blocked by PDIs and are less common in patients accustomed to dopamimetic treatment.  The other side effects are infrequent and neither serious nor life-threatening \cite{Connolly_2014}. When given with adequate PDI pretreatment, intravenous levodopa has minimal if any cardiovascular effects \cite{Siddiqi2015}. The overall safety record is perhaps expected since L-DOPA is, after all, an amino acid present in the normal human brain. 

The safety of IV levodopa is important for patients but also for regulatory review.  Changing the route of administration of a drug in a research study necessitates submitting an IND application if changing the route of administration "significantly increases the risks \dots\ associated with the use of the drug product" (\href{http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.2}{\S 21 CFR 312.2(b)(iii)}).  The data summarized here suggest that intravenous administration of levodopa does not significantly increase the risks of levodopa compared to oral administration.  In summary, studies conducted throughout the past half century support the safety of IV levodopa administration in human patients.
  

\section{Acknowledgments}\label{acknowledgments}

The authors gratefully acknowledge the assistance of Beth Beato.

Manuscript preparation was funded in part by the National Institutes of
Health (K24 MH087913).

An early summary of this work was presented at the World Parkinson
Congress, Washington, DC, USA, February, 2006. The poster is
\href{http://f1000.com/posters/browse/summary/1097795}{archived at F1000
Posters 6:268, 2015}.

A preprint is being submitted simultaneously to
\href{http://peerj.com/KBMD}{PeerJ PrePrints}.

\section{Author contributions}\label{author-contributions}

Literature search: SHS, CLG, NKA, CD, KJB

Writing: SHS, CLG, KJB

Translation from German: MK

All authors reviewed and approved the final draft.

\section{Competing interests}\label{competing-interests}

Author KJB is Sponsor-Investigator for Investigational New Drug (IND)
application \#69,745 for intravenous levodopa (U.S. FDA).

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