Optimizing oral levodopa delivery by prolonging duration of effect remains a key challenge in managing OFF periods in Parkinson’s disease. IPX203 is an oral modified-release formulation combining immediate-release (IR) and extended-release (ER) levodopa with IR carbidopa, designed to provide rapid onset and sustained exposure. We characterized pharmacokinetics of levodopa and carbidopa following IPX203 compared with IR and controlled-release (CR) levodopa/carbidopa using population pharmacokinetic modeling from a Phase 1 study in healthy volunteers. Plasma concentration–time data were analyzed using nonlinear mixed-effects modeling. Formulation-specific absorption models, including a dual-depot model for IPX203, were combined with a shared systemic disposition model. The models adequately described observed levodopa and carbidopa concentrations across formulations. Marked formulation-dependent differences in levodopa exposure were driven by absorption. IR-levodopa/carbidopa produced rapid absorption with peak concentrations followed by a steep decline, consistent with elimination-rate–limited pharmacokinetics. CR-levodopa/carbidopa showed delayed absorption with lower peak concentrations and limited time within the expected therapeutic range (750–1000 ng/mL). In contrast, IPX203 exhibited biphasic absorption, with an initial IR-driven peak and sustained concentrations from the ER component, consistent with rate-limited absorption and prolonged intestinal residence. This resulted in reduced peak–trough fluctuation and longer duration within therapeutic range. Carbidopa profiles were qualitatively similar, with higher absolute exposure for IPX203. Model-based simulations of commonly used dosing regimens suggested that IPX203 administered every 6 h achieved the most stable levodopa concentrations. These findings indicate that IPX203 provides a distinct exposure profile characterized by rapid onset and sustained levodopa exposure driven by controlled absorption.

This concise, yet authoritative, clinical reference guide fulfils the needs of diverse clinicians, pharmacists and allied health professionals prescribing for Parkinson's disease and movement disorders in contemporary clinical practice. With chapters on newly approved drugs and their effects on motor and non-motor symptoms, information is also given on their use in particular populations including the elderly and patients with cognitive impairment. Each chapter includes pharmacological/biochemical rationale for drug use, a general guide to therapeutic use, pharmacokinetics, interaction profile, adverse effects, dosing and use, special population considerations, costs and value for money considerations, clinical vignette, a summary overview, and suggested reading. Ordered alphabetically and perfect for quick reference use, the guide is practical and essential for all prescribers with responsibility for patients with Parkinson's disease, including neurologists, geriatricians, internists, neurosurgeons, psychiatrists, family physicians, pharmacists as well as allied health professionals and resident, fellow, and student trainees in all related medical fields.

Enhancing levodopa efficacy through peripheral COMT inhibition and using continuous infusion are both established strategies for managing motor fluctuations. Both approaches aim to improve the pharmacokinetics of levodopa in order to maintain a steady delivery of levodopa to the brain, avoid the deep troughs in levodopa plasma concentrations associated with oral levodopa delivery, and thereby reduce OFF time. In this review, we describe the pharmacologic rationale for combining COMT inhibition with entacapone and continuous dopaminergic delivery that led to the development of levodopa/entacapone/carbidopa intestinal gel (LECIG). Entacapone is a peripheral COMT inhibitor, that effectively reduces the metabolism of levodopa to 3-O-methyldopa and increases the amount of levodopa that can be transported into the brain. However, entacapone has a short half-life and poor oral bioavailability that necessitates frequent dosing for optimal efficacy. Continuous infusion of entacapone allows for improved bioavailability from direct delivery to the duodenum/jejunum. As such, lower overall levodopa doses can be given to achieve therapeutically effective concentrations. Accumulating real-world evidence with LECIG supports its use in managing motor fluctuations in patients whose control is becoming suboptimal with oral approaches. We provide an overview of the growing evidence base for its risk-benefit profile in patients with motor fluctuations.

Apomorphine is the only dopamine agonist used to treat Parkinson disease with similar efficacy to levodopa. Its original characterization as a dopamine agonist was based on its receptor binding profile and capacity to recruit G proteins; however, current knowledge of G protein-coupled receptors highlights the importance of β-arrestin signaling to dopamine receptor functionality and expression. This study systematically compared the activity of apomorphine and dopamine across the range of dopamine receptor subtypes using biosensor assays that assessed its functional effects on both the cAMP and β-arrestin signaling pathways. Apomorphine facilitated cAMP signaling at both D1 and D2 family receptors with similar efficacy to dopamine but greater potency except at D3 receptors, where it exhibited similar potency. Apomorphine also recruited β-arrestin at all dopamine receptors similar to dopamine but with lower maximal effects at D1, D4, and D5 receptors. The potent efficacy of apomorphine on cAMP signaling at all dopamine receptor subtypes may explain its similar efficacy to levodopa. The clinical impact of the β-arrestin effects requires further study but is likely to influence its pharmacodynamic effects, including differences in adverse event profile compared to levodopa and D2-preferring agonists.

In levodopa treated patients with Parkinson’s disease (PD), the standard approach to managing motor fluctuations is to adjust dopaminergic therapy. However, despite the availability of a wide armamentarium of dopaminergic medications, most patients treated with levodopa will still experience significant OFF time, and it is increasingly clear that motor fluctuations have a significant non-dopaminergic component. In this narrative review, we compare and contrast the therapeutic profiles of the only two non-dopaminergic medications approved in the US for the management of OFF time, namely amantadine and istradefylline. When compared against each other the two agents exemplify two different pharmacological approaches to treatment. Whereas amantadine has a multimodal pharmacology, istradefylline has highly specific actions at A2A receptors which are highly expressed in the indirect pathway of the basal ganglia. We discuss how both offer an important alternative approach to treatment, without increasing total dopaminergic load. Clinicians can also consider that amantadine and istradefylline each have overlapping indications with classic dopaminergic medications, but with distinct mechanisms of action that can complement each other to reduce motor complications in patients already being treated with other dopaminergic agents.

The symptomatic treatment of Parkinson's disease (PD) has been dominated by the use of dopaminergic medication, but significant unmet need remains, much of which is related to non-motor symptoms and the involvement of non-dopaminergic transmitter systems. As such, little has changed in the past decades that has led to milestone advances in therapy and significantly improved treatment paradigms and patient outcomes, particularly in relation to symptoms unresponsive to levodopa. This review has looked at how pharmacological approaches to treatment are likely to develop in the near and distant future and will focus on two areas: 1) novel non-dopaminergic pharmacological strategies to control motor symptoms; and 2) novel non-dopaminergic approaches for the treatment of non-motor symptoms. The overall objective of this review is to use a 'crystal ball' approach to the future of drug discovery in PD and move away from the more traditional dopamine-based treatments. Here, we discuss promising non-dopaminergic and 'dirty drugs' that have the potential to become new key players in the field of Parkinson's disease treatment.

James Parkinson (1755– 1824) left the world a notable legacy when his ‘Essay on the Shaking Palsy’ was published in 1817. Parkinson's description of the symptoms of what, as first suggested by Charcot in his famous Tuesday lectures at the Salpêtrière in Paris, came to be known as Parkinson's disease (PD) is a masterly exercise in close and acute observation, based on study of just six people (several of whom the author met in the street). In 2016, almost exactly 200 years later, the total number of people diagnosed with PD worldwide was estimated at 6.1 million with an estimated increase to above 12 million over the next generation [1]. To that direct burden of illness may be added the burden of care assumed by many millions of relatives and friends. The clinical presentations and patterns of progression of PD differ widely between individual patients and, with the exception of genetic subtypes, the underlying cause for such heterogeneity is poorly understood. Indeed, it has been argued (albeit as an openly acknowledged appeal to the extreme) that such is the variability of presentation and impact on individuals there are in effect as many different variations of PD as there are patients [2]. A corollary of this is that, even within the limitations of the existing medical armamentarium, the choice of therapy is a highly individual and shared decisionmaking exercise that has to take into account the type and severity of motor and nonmotor symptoms, age, comorbidities, and other patientrelated factors— not least patient preferences. For the foreseeable future, however, any suggestion that we can deliver a PD treatment package personalized to the exact pathophysiological circumstances of an individual patient would be to overpromise. Advances in our understanding of the processes of neuronal degeneration [3] have identified a range of possible targets for preventive interventions in PD [4], with interest in particular currently directed towards decreasing the toxicity of various forms of alphasynuclein [5]. This research holds great promise for the future but has yet to translate to approved new therapies for PD. One thing that has changed in recent years, and with it changed our conception of PD, is the recognition that nonmotor symptoms are a significant component of PD whose appearance may even precede the motor symptoms. (Perhaps not surprisingly, Parkinson recognized the importance of nonmotor phenomena 200 years ago, but we chose to largely ignore his teaching.) However, from a symptomatic treatment perspective, PD remains emphatically a motor disorder and treating the motor symptoms is at the core of the medical response. Levodopa remains the cornerstone of drug treatment for motor symptoms more than 50 years after its introduction and is required eventually by almost all patients, conferring improved motor function and quality of life. To maximize the effectiveness of levodopa, we have introduced selective enzyme inhibitors to control its metabolism and to optimize its therapeutic effect. Wellestablished examples are the use of decarboxylase inhibitors to inhibit peripheral metabolism and inhibition of monoamine oxidase B to potentiate the effect of the dopamine derived from levodopa. The third and key component of levodopa's metabolism, inhibition of catecholOmethyltransferase (COMT), has been tackled only more recently. The incorporation of the peripheral COMT inhibitor entacapone with levodopa and the decarboxylase inhibitor carbidopa into Stalevo® is a working example of the value and importance of easytouse and effective combination therapies for PD. The US Food and Drug Administration approved in June 2003 the triplecombination tablet for the treatment of patients with idiopathic PD who experience signs and symptoms of endofdose "wearing off". In the same month, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products also issued a positive opinion of the combination tablet. On the basis of those regulatory endorsements, Stalevo® entered clinical use in the United States in late 2003 and in Europe at the start of 2004. The total cumulative exposure of PD patients to either the combination (Stalevo®) or its entacapone component now exceeds 6 million patientyears, and it is firmly established as a valued element in the medical repertoire for patients experiencing wearing off from the traditional therapy. This supplement reviews the development and evolution of Stalevo® in its first 20 years.

Dopaminergic therapy for Parkinson's disease has revolutionised the treatment of the motor symptoms of the illness. However, it does not alleviate all components of the motor deficits and has only limited effects on non-motor symptoms. For this reason, alternative non-dopaminergic approaches to treatment have been sought and the adenosine A2A receptor provided a novel target for symptomatic therapy both within the basal ganglia and elsewhere in the brain. Despite an impressive preclinical profile that would indicate a clear role for adenosine A2A antagonists in the treatment of Parkinson's disease, the road to clinical use has been long and full of difficulties. Some aspects of the drugs preclinical profile have not translated into clinical effectiveness and not all the clinical studies undertaken have had a positive outcome. The reasons for this will be explored and suggestions made for the further development of this drug class in the treatment of Parkinson's disease. However, one adenosine A2A antagonist, namely istradefylline has been introduced successfully for the treatment of late-stage Parkinson's disease in two major areas of the world and has become a commercial success through offering the first non-dopaminergic approach to the treatment of unmet need to be introduced in several decades.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson’s disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the ‘gold standard’. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa–carbidopa intestinal gel, and levodopa–entacapone–carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.

BackgroundTo compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. ObjectivesTo update LED conversion formulae based on a systematic review. MethodsThe MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. ResultsThe systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. ConclusionsThe LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo ® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.

Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson’s disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients’ motor and non-motor symptoms, reduce “OFF” time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.

The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.

The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson’s disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current ( I sc ) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

INTRODUCTION:Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.AREAS COVERED:Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment.EXPERT OPINION:This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1–4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.