Can Continuous Levodopa Delivery Be Achieved in the Absence of Intrajejunal Levodopa Infusion? Implications for India and Underserved Countries

Continuous drug delivery (CDD) in Parkinson ’ s disease (PD) aims to achieve continuous dopaminergic stimulation (CDS) and, in theory, aims to mimic physiological tonic, rather than phasic, stimulation of the striatal dopamine receptors. 1 In animal models, the concept has been shown to substantially reduce motor ﬂ uctuations and speci ﬁ cally dyskinesias; although in humans the evidence has been less robust, as dyskinesias or “ off ” periods break through in the long term. 2 Physiologically, the tonic ﬁ ring of dopaminergic neurons in the substantia nigra pars compacta ensures that striatal dopamine levels are maintained relatively constant. 3,4 However, the pulsatile phasic dopaminergic stimulation given by intermittent oral levodopa intake induces molecular and physiological changes in the neurons of the basal ganglia, and this is considered primarily responsible for the development of motor complications such as dyskinesia and “ wearing off ” . 5,6

1990s and is available in most countries only to the affluent patients who can afford the cost of this treatment.
Despite being developed in the 1960s, levodopa remains the most effective therapy for PD.It is affordable to a global PD population and not only to citizens of developed and wealthy countries, as applicable to the current device-aided therapies.A discussion on latest developments in levodopa delivery and its affordability is, therefore, relevant in a global context.LCIG infusion, in particular, is one of the most effective therapies in advanced PD, with recent data suggesting efficacy shown for at least 13 years in advanced PD as well as in a small cohort of parkinsonian patients with progressive supranuclear palsy. 18,19Next to these established treatment strategies, several new device-aided therapies have been tested in phase 3 randomized controlled trials with positive results and wait formal licensing.These include levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion (already approved in several countries), subcutaneous levodopa/carbidopa, 20 and subcutaneous foslevodopa/ foscarbidopa preparations, [20][21][22] which are soon to enter the market with the aim to mimic CDS.
Non-levodopa formulations that may be able to provide CDD and in current use include apomorphine subcutaneous infusion and transdermal rotigotine patch, but they will not be discussed in detail in this article.

The Economic Burden of CDD
The progress made in CDD with device-aided therapies comes at high costs and requires healthcare systems able to absorb the highly expensive maintenance of such therapies, making these available only in selected, high-income countries, and to affluent patients of underserved countries.If one considers the patient community in India as an exemplar for a lower-middle-income country, the cost for a 500 mg/day regimen of oral levodopa is $60 USD/year.However, the average salary in India ranges approximately from $1660 to $2680 USD/year, 23 with a minimum national wage of approximately $760 USD/year. 24Unless government funded, even oral levodopa therapy may be unaffordable to many Indian patients.Therefore, device aided therapies remain out of bounds for most such patients, although clinical needs are inevitable.As an example, the approximate cost of apomorphine therapy in India ranges between $3665 and $4887 USD/year, whereas, for DBS, the overall expenditure for a DBS procedure with a rechargeable device and maintenance with an average of 15 years of life is $1833 to $2444 USD/year (information gathered by local experts).Moreover, the cost of LCIG infusion per patient per year in India is equivalent to $39,075 USD/year, 25 hence, potentially prohibitive, despite being considered the most effective form of levodopa replacement in advanced PD.In addition, on average, 300 new patients attend a movement disorder clinic every year 26 in India and, as such, the economic burden of advanced therapies makes these unaffordable for most patients.In essence, the vast majority of advanced patients with PD in underserved countries such as India remains, and continues to remain, inadequately treated.This fact shines a light on the growing issue of inequalities in the access to optimal and bespoke healthcare, which are driven by poverty, scarcity of resources, and by the soaring costs charged by pharmacological industry for their products and technology.

Existing Inequalities In Research and Healthcare
Another aspect to consider while addressing inequalities of care in the context of CDD is that even the most recent long-acting levodopa-based treatments, such as IPX-203 (a new extended release levodopa/carbidopa), 27 subcutaneous levodopa/carbidopa or foslevodopa/foscarbidopa, 28 as well as the Accordion Pill (delivery based on gastric retention of multilayer films containing immediate-and controlled-release levodopa/carbidopa) 29 among others, have been investigated in clinical trials recruiting almost entirely White patients, with a small number of patients belonging to ethnic minorities. 30This has been recently highlighted by a study conducted by Lau and colleagues, 30 showing that the inclusion of under-represented ethnic minorities groups in recently published clinical trials for PD is only 21.57%, and is not even considered in most studies.This constitutes a severe underrepresentation when compared to the proportion, for example, of Black or African American in the UK and United States (US) population. 30ther examples include clinical trials addressing cognitive impairment in PD conducted in the past 5 years, where more than 90% of recruited participants were White and non-Hispanic. 31These findings add to the already existent inequalities in research in PD where, for example, also women are underrepresented beyond what expected from the lower prevalence of PD in this group. 32thnic disparities of care are also observed in daily clinical practice, as demonstrated by the reduced prescription of analgesics for PDrelated pain in Black patients when compared to White patients with similar pain ratings. 33Apart from the societal relevance of inequality, there may also be pharmacogenetic, cultural, and other racial differences in drug metabolism and eligibility for treatment (as highlighted during the coronavirus disease 2019 pandemic) 34 and these cannot be addressed by clinical trials conducted in the White population only (Fig. 2).

A Four-Level Solution
How can, therefore, the massive and glaring inequalities of care in the context of levodopa-based CDD strategies denying bespoke advanced therapies to hundreds of patients in need be addressed?One potential strategy may be to explore whether levodopa-based CDS can be achieved in the absence of expensive therapies.We propose a four-level solution encompassing the following: (1) extend the action of levodopa; (2) improve the absorption and transport of levodopa; (3) consider the use of Mucuna pruriens (MP); and (4) reduce the cost of validated delivery systems (Fig. 3).

Level 1: Extend Levodopa Action
Levodopa and dopamine are metabolized by several enzymes, such as dopa decarboxylase (DDC), COMT, monoamine oxidase (MAO), and aldehyde dehydrogenase (ALDH), causing overall peripheral and central degradation and reduction of dopamine available to the nigrostriatal pathway. 35Carbidopa and benserazide were developed to counteract the action of the peripheral DDC responsible for the conversion of levodopa to dopamine at the systemic level. 36DDC inhibitors are an integral part of any levodopa-based regimen, being responsible for a 10-fold increase in central nervous system levodopa availability. 35ral levodopa with DDC inhibitors is available globally and is often the only therapy available to PD patients.Central MAO type B and COMT enzyme inhibitors are also in widespread use in developed countries.Among MAO-B inhibitors, rasagiline is the most available and commonly used because of lack of amphetamine-like activity or affinity for any of the catecholaminergic or serotonergic receptor groups, compared to selegiline. 35In addition, a controversial preclinical and clinical evidence suggest a potential neuroprotective role for rasagiline. 37,38COMT inhibitors have also been used to increase the "on" time while managing motor fluctuations in patients with PD.In particular, the secondgeneration inhibitor entacapone and, more recently, the thirdgeneration opicapone have become the most used because of their effectiveness and lack of serious adverse events such as liver toxicity.0][41] However, it is expensive and unlikely to be affordable for patients in developing countries.Improving the overall bioavailability of levodopa with the appropriate use of MAO-B and COMT inhibitors has, therefore, the ability to provide a dopaminergic stimulation profile that is more stable and semi-continuous, therefore, mimicking, at least in part, the CDD stimulation modality.In underserved areas, however, only compounds that are now available in generic forms may be available for prescription.In India, rasagiline, selegiline, safinamide, and entacapone are currently available.Local and learned societydriven clinical guidelines should provide guidance on this strategy.

Level 2: Improve Levodopa Absorption and Transport
Levodopa is characterized by limited oral bioavailability and extremely short half-life, therefore, representing one of the most difficult molecules to control pharmacologically. 11Part of its limited bioavailability, as previously discussed, lies in the numerous metabolic pathways and enzymatic degradations encountered across its journey from the GI tract to the brain, beyond the blood-brain barrier.GI dysfunction, in addition, is a cardinal nonmotor symptom 42 and a feature of the recently described noradrenergic subtype of PD, 43 which adds to the overall challenge of levodopa absorption when administered orally, due to both absorption as well as transport barriers.Addressing these obstacles with relatively cheap lifestyle-and diet-based advice would, therefore, result in better bioavailability of oral levodopa and, subsequently, in a less discontinuous dopaminergic stimulation. 11arriers to absorption are represented by the action of human and bacterial decarboxylases, 44,45 the saturable facilitated transport system, where levodopa competes with other dietary amino acids, 46 the peripheral COMT action, and small intestinal bacterial overgrowth. 47In addition, Helicobacter pylori (H.pylori) infection may impair levodopa absorption by various mechanisms, although the role of its eradication in improving the motor effect of oral levodopa is disputed, there being evidence both for and against. 11,48I barriers to levodopa transport include dysphagia, esophageal alterations, delayed gastric emptying, 49 slow transit, and outlet constipation. 11Prompt management of these issues, together with H. pylori screening and eradication, can therefore, prove to be an effective strategy to improve the bioavailability of levodopa.
Further contribution to this issue can be given by the identification of "dos and don'ts" in relation to levodopa therapy and food, therefore, triggering specific dietary and lifestyle interventions (Fig. 4).Among the "dos", for example, the intake of levodopa, particularly in the dispersible form, with orange juice or carbonated drinks augmented by dispersible vitamin C tablets, 50 may facilitate its overall absorption.Another possible "do" is represented by the "sip technique" and flask-based therapy, consisting in the intake of dispersible levodopa/carbidopa dissolved in water, 51 stored in a flask protected from direct light and at room temperature, and sipped at regular intervals and/or at night (Fig. 5).This may address the "delayed on" or the "no on" periods, as well as nocturnal akinesia (Chaudhuri and Batzu, personal observation).3][54] It is important to note, however, that this technique has some limitations, including reduced stability with high temperatures and variability of levodopa dose associated with each "sip."Relevant "don'ts" in the levodopa-food relationship include food consumption, and particularly proteins, less than 30 minutes before or after levodopa intake, 11 meals with high protein content, 55 and diet with high dairy intake. 56

Level 3: Mucuna Pruriens
Despite being the primary treatment for PD for over 50 years, the global standard of levodopa with a DCC inhibitor remains unavailable and/or unaffordable in many Sub-Saharan African countries and several other low-income countries. 57,58MP is a wild leguminous plant commonly found in tropical regions, containing a levodopa concentration between 0.81% and 9.49%. 59,60t is commonly found at low cost in local markets as soil fertilizer or as a remedy against male infertility. 61It has recently been proposed the use of MP to replace, or as add-on to, other dopaminergic treatments because of its low cost and wide availabilty. 61Because of its recent re-discovery in the context of natural remedies and non-conventional therapies for PD, MP is also often sold in high income countries at high costs.In recent years, however, its potential as affordable and easyto-produce treatment for PD where levodopa is unavailable has initiated several research studies aiming to prove the feasibility, efficacy, and cost effectiveness of MP-based therapeutic regimens.It has been estimated that 7 g of MP roasted powder obtained without any pharmacological processing is able to provide 400 mg of DDC inhibitor-free levodopa, approximately equivalent to 100/25 mg of levodopa/carbidopa, for a total annual cost per patient of $10 to $15 USD (against $365 USD/year for standard levodopa/DDC inhibitor in Sub-Saharan Africa and a population living with less than $2 USD/day). 59,62In a double-blind, randomized, controlled crossover trial, single-dose MP intake met all non-inferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. 63 In addition, high-dose MP (levodopa concentration of 17.5 mg/kg) gave similar clinical effects to the same dose of levodopa alone, with better tolerability profile. 63P, however, is also available online and the prescriber needs to be aware of the dose conversions that relate to commercial levodopa.

VIEWPOINT
Level 4: Making CDD More Affordable Another option to consider when addressing the need of CDD in the absence of device-aided therapies is the potential delivery of dispersible levodopa/benserazide as liquid solution by a syringe through a percutaneous endoscopic transgastric gastrostomy (PEG) or jejunostomy (PEG-J).PEG-Js are currently performed to allow LCIG infusion through an expensive pump system, but the cost of the procedure only, despite being a minor surgery, is not prohibitive.In this way, when liquid levodopa is provided at close time intervals, effects similar to LCIG may be observed, therefore, mimicking CDD.In the context of administering the drug beyond the stomach (as in the case of a PEG-J), dilution of the medication with sterile water is advised. 64Tablets can be dispersed in 10 mL of water to give a cloudy white dispersion and particular attention should be given in avoiding concomitant food intake. 64urthermore, increasing the affordability and accessibility to device-aided CDD in underserved areas might benefit from the exploration of additional strategies: localized manufacturing, governmental support mechanisms, and integration within insurance frameworks may provide insights into innovative approaches that may alleviate the economic barriers associated with the adoption of device-aided therapies such as LCIG.For example, when considering India's recognized status as global hub for pharmacological manufacturing, the prospect of local production while maintaining high quality presents a substantial opportunity to significantly reduce associated costs.In such scenario, local community entities, support organizations, and patient groups can also play an instrumental role in advocating for policy reforms that prioritize subsidized pricing or even cost-free provisions of CDD through government-affiliated healthcare centers.

Alternatives To Levodopa
Despite their important role in providing CDD, apomorphine subcutaneous infusion and rotigotine transdermal patch are still expensive in the context of developing countries and mostly not available or, especially in the case of rotigotine, often available through alternative channels.However, there is the potential to develop local technologies for the production of rotigotine and apomorphine, particularly considering the relatively lower manufacturing costs associated with apomorphine and the related infusion system.Indeed, apomorphine was originally developed for clinical use in the United Kingdom when local pharmacies prepared and delivered apomorphine for clinical studies reported in the 1980s and early 1990s. 65f note, strategies aimed at reducing DBS costs and the utilization of alternative, more affordable surgical therapies can contribute to optimizing the management of patients in need of continuous treatment.For instance, the cost-effectiveness of non-rechargeable implantable pulse generators in comparison to rechargeable counterparts may facilitate the dissemination of DBS within low-income regions. 66Moreover, although there is a preference for DBS and newer techniques like magnetic resonance imaging-guided focused ultrasound in higher-income nations, other ablative surgical techniques, such as radiofrequency thermoablation, and stereotactic radiosurgery, should be considered in situations where patients need to selffinance, as often occurs in lower-middle-income countries.

Conclusions
Reducing inequalities in healthcare should be a primary objective for any healthcare policy, learned society, and patient charity.PD is the fastest growing neurodegenerative disorder and the highest increase in prevalence will involve lowermiddle and low-income countries, where life expectancy has increased in the past decades.In this scenario, it is irresponsible to ignore the urgent need to address not only the basic aspects of PD-related management, but also the challenges of advanced PD, including motor and non-motor fluctuations and, therefore, the necessity of making CDD available.Although clinical guidelines based on Western and developed countries espouse the use of advanced therapies based on clinical criteria, the unavailability of such therapies in vast parts of the world and to needy patients is often ignored.The solution to this problem is not an easy one, and may require a financial and political decision-making process with relevant stakeholders such as industry, policy-making bodies as well as patient advocacy groups.Although policy makers and healthcare systems adapt to these long-term objectives, it is essential to provide acceptable and realistic options in the meantime.We have, therefore, proposed a few, essential strategies that can support the need for CDD and, more in general, optimal dopaminergic stimulation in the absence of LCIG and other device-aided therapies.We suggest researchers to undertake clinical trials using some of these strategies to provide robust evidence for management, as it has been shown in the MP studies.Research should also take the role of tackling the current barriers in trial participation for underserved communities and low-income areas with, for example, increased funding directed to bespoke local outreach strategies and direct contact with primary care physicians to overcome the barriers of sporadic specialist referrals.Increasingly large industry manufacturers of molecules to manage PD need to be aware of health inequalities issues and address pricing of medications so that costs are not prohibitive to a vast number of PD patients in the world.This issue currently remains a major unmet need, where learned societies and government policy makers can play an important part.In addition, industry stakeholders have also the responsibility to address recruitment inequalities in clinical trials for PD and the lack of data in many underserved countries.In a similar way, academic institutions need to consider investigator-led clinical trials looking at feasible, real-life, culturally bespoke, and countryspecific therapies that can benefit thousands of patients worldwide.It is a "long and winding road" and yet a necessary one toward real equality and treatment opportunities for all people with Parkinson's disease.

FIG. 1 .
FIG.1.Annual healthcare costs are significantly higher for patients with advanced PD in EU5 countries (Spain, Italy, United Kingdom, France, and Germany).10PD, Parkinson's disease.