Levodopa: 50 and Fabulous

The gold standard of Parkinson’s disease management has just entered its Golden jubilee. In the 1960s, Arvid Carlsson linked the depletion of striatal dopamine with Parkinson’s disease. By 1969, Donald Calne and Melvin Yahr confirmed that levodopa improves bradykinesia, rigidity, and tremor in patients with postencephalitic and idiopathic Parkinson’s disease, and from 1969 through the mid-1970s the evolution of levodopa literally awakened the scientific community to profound possibilities of improvement but tempered with practical pessimism when side effects emerged, as documented by Oliver Sacks.1

“For a certain time, in almost every patient who is given levodopa, there is a beautiful, unclouded return to health; but sooner or later, in one way or another, almost every patient is plunged into problems and troubles. Some patients have quite mild troubles, after months or years of good response; others are uplifted for a matter of days—no more than a moment compared to a life-span—before being cast back into the depths of affliction.” This is an excerpt from Oliver Sacks’ book Awakenings that captures the double-edged sword that is levodopa. From a medical economic perspective, levodopa is one of the most cost-effective medications ever developed in treating a chronic neurodegenerative disease.2 It is an excellent therapy but not without it’s drawbacks. In fact, frequent dosing and continued use leads to complex motor and cognitive concerns. Since the time it was discovered, the fundamental formula has not changed. That said, its method of delivery has evolved and continues to evolve for the purpose of preventing side effects.

Pharmacology and Current Use

Levodopa is finicky in its pharmacology. Dopamine cannot cross the blood brain barrier but levodopa (its precursor) can. This led to a problem with tolerability since an extraordinary amount of levodopa was needed to achieve a small penetrance across the blood-brain barrier, and this lead to side effects, notably nausea and emesis. The first advancement was the development of peripheral decarboxylase inhibitors such as carbidopa, so that lower doses of levodopa could be effectively used while preventing emesis (Sinemet = sin (without) / emesis (vomiting)).2 This was brought to market in 1975. The oral form of immediate release Sinemet needs to be taken every few hours, so the next logical advancement was a continuous release formulation, which followed in 1989. However, continuous release levodopa was quickly found to be problematic in its absorption, which impacted its consistency and reliability of on an off times. In 1998, the first COMT inhibitors became commercially available and in 2003 a combination of Sinemet + COMT inhibitors came to market as Stalevo.3 This was quickly followed in 2006 by Azilect. The common theme in the evolution of levodopa was to mimic the natural steady state of dopamine release, since pulsitile delivery has been implicated in the development of side effects.3

One of the common questions patients often ask is, “Will my body get used to levodopa and it won’t be effective anymore?” Clinical observations are supported by numerous clinical studies that after four to five years of levodopa use, between 40 to 75 percent of patients develop motor fluctuations.4 It is not that patients become “used” to the medication, but rather a function of real estate and the loss of dopaminergic neurons as the disease naturally progresses. There are just less neurons to take up levodopa and convert it into dopamine which can then be stored and slowly released. As less and less neurons are functional, this storage and slow release becomes less predictable and more medication is required to achieve a clinical response.3

No medication has been developed to slow or reverse the loss of dopamine neurons. Additional research has suggested that pulsatile delivery of levodopa can also predispose patients to motor fluctuations due to post synaptic changes in the basal ganglia that occur overtime.3 Early on the idea of continuous delivery was broached but initial trials with IV infusions were stopped due to thrombus formation, but this pulsatile delivery is the modifiable variable which has led to the most recent changes is Levodopa therapy. The most recent, clinically available changes in the delivery of Levodopa are Rytary and Duopa.

Rytary. A novel extended release LD/CD capsule, Rytary contains immediate and sustained release pellets which gets absorbed at different rates along the GI tract. Pharmacokinetic studies showed that this allowed for a plasma concentration above 50 percent of Cmax for four hours as compared to 1.4 hours of Sinemet IR.3 This could potentially increase an interval to six hours between doses. Clinically this has not always been achieved, and it is important to note that the delivery is actually multiple capsules at each dose depending on the patient’s converted IR dose. Rytary is a product of Impax Pharmaceuticals and the company does provide samples of the medication for the patients to use while titrating to their preferred dose.

Duopa. Levodopa Carbidopa Intestinal Gel was first investigated in 1993. The first attempt at enteral infusion was in 1993. It has been available in Europe as Duodopa for over a decade and was recently approved in the US in 2016. Bioavailability studies have shown that this delivery best mimics the natural dopaminergic state. Duopa is a gel form of levodopa that in a concentration of 20mg/5ml continuously infused over 16 hours. It involves the placement of a PEG-J and most complications arise from tubing and pump issues. A number of randomized clinical trials have been conducted in patients selected for enteral infusion in the setting of motor fluctuations, comparing active infusion to placebo and active infusion to best oral therapy. Those receiving the enteral infusion had an improvement in on time without troublesome dyskinesias for close to two hours with an improvement in quality of life scores.5

In the Pipeline

Novel delivery systems in the pipeline include the accordion pill, transdermal patches and pumps, and intranasal sprays.

Accordian Pill. Intec Pharma is developing a novel gastro-retentive delivery system (Accordian Pill) of carbidopa/levodopa and just completed a Phase 2, randomized, multiple-dose, multi-center, open-label, dose-ranging crossover study in 60 PD patients. According to their website and pipeline development, the AP-CD/LD doses tested ranged from 250-500mg of levodopa over a seven to 21 day period given once or twice a day.6 Results of the study showed a reduction in total OFF Time was achieved without increasing the ON Time with Troublesome Dyskinesia and with decreasing Total ON Time with Troublesome Dyskinesia between two and hours hours daily in comparison to current optimized LD treatment. These improvements were achieved with significantly less number of LD doses per day.

Subcutaneous Levodopa Delivery. ND0612 is a subcutaneous deliver of up to 360mg of levodopa over a continuous 24-hour infusion of a patch/pump device as described by Poewe in 2015.7 Phase 1 studies showed stable plasma levels and good local tolerability. On Neuroderm’s website in pipeline products and there is also a belt/pump version ND0612L and ND0612H for moderate and severe Parkinson’s disease—delivery and device symptoms very similar to insulin pump infusion therapies.8 These are being looked at as an alternative to enteric delivery and Deep Brain Stimulation. They have completed two Phase 2 studies so far. One was a single-dose, 24-hour continuous-administration, randomized, double-blind, placebo-controlled study on eight subjects with moderate Parkinson’s disease. Results showed that subcutaneous delivery of ND0612L was safe and tolerable, and achieved steady-state plasma levodopa concentrations of 700-900 ng/ml (which is estimated to be within the typical therapeutic range). The other was a study enrolling 30 patients suffering from motor complications. Final results of this Phase 2 study showed that patients with moderate to severe Parkinson’s disease who received continuous, subcutaneous doses of ND0612L exhibited clinically significant reduction in fluctuations of plasma levodopa concentrations compared to patients receiving placebo.

Intrapulmonary Levodopa Delivery. CVT-301 is a self administered inhaled form of levodopa and the closest to clinical use having just completed a Phase 3 study with a new drug application submission planned for the second quarter of 2017.9 Intrapulmonary drug delivery can lead to rapid effective plasma concentrations of medications and makes it ideal for “rescue” medications. For patients with unpredictable off periods, “rescue” medications are imperative for symptoms relief. Currently an injectable form of apomorphine, Apokyn, is used in the reguard (but this is getting a makeover as well and a sublingual dissolvable apomorphine strip is in development). Acorda Pharmaceuticals sponsored the SPAN-PD trial which met it’s primary endpoint: CVT-301 showed statistically significant improvement of motor function compared to placebo. CVT-301 is a self-administered, inhalable formulation of levodopa. A Phase 3 clinical trial of 339 participants who received CVT-301 or placebo as an adjunct to their oral carbidopa/levodopa regimen showed a statistically significant improvement in motor function in people with Parkinson’s disease experiencing OFF periods. This was based on the change at Week 12 in Unified Parkinson’s Disease Rating Scale-Part 3 (UPDRS III) score. The patients will have to load a capsule into the inhaler chamber and when the mouthpiece is pushed down, the capsule is punctured and its contents inhaled—in this method 50 mg of levodopa is delivered achieving peak plasma levels in 15 minutes correlating to therapeutic effect in five to 10 minutes. A non-invasive rescue therapy is encouraging, though dexterity in assembling the inhaler may be a practical limiting step in a patient who is “off” and while this is self administered, there may still need to be a care partner present to help.

Conclusion

While levodopa continues to be re-imagined and its aging delivery gets a face-lift, one glaring omission needs to be addressed: dopamine deficiency is only one aspect of the complex pathology of Parkinson’s disease. Multiple neurotransmitters are depleted or altered resulting in the complex phenotype of motor, cognitive, and behavioral symptoms that is Parkinson’s disease.

The advancements of maximizing levodopa therapy are necessary and promising, but their impact will be incomplete if additional attention is not also paid to their complementary compounds such as norepinephrine and serotonin.2 As with all aspects and management of Parkinson’s disease, combining multiple treatment strategies is most effective. n

Jill Giordano Farmer, DO, MPH is an Assistant Professor of Neurology at Drexel University Department of Medicine, where she is also Director of the Parkinson’s Disease & Movement Disorder program.

1. dos Santos-Lobato, B. L. (2016). Harbinger of storm: influence of Oliver Sacks on Levodopa therapy in early 1970’s. Arq Neuropsiquiatr, 687-689.

2. Lewitt, P. (2015). Levodopa Therapy for Parkinson’s Disease: Pharmacokinetics and Pharmacodynamics. Movement Disorders, 64-72.

3. Hauser, R. (2009). Levodopa: Past, Present, and Future. European Neurology, 1-8.

4. Ahlskog JE, e. a. (2001). Frequency of Levodopa Related Dyskinesias and motor fluctuations as setimated from the cumulative literature. Movement Disorders, 448-458.

5. Olanow CW, e. a. (2014). Continuous Intrajejunal levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomized, controlled, doubl blind, double dummy study. Lancet Neurology, 141-149.

6. Intec Pharma. (n.d.). Retrieved from Intect Pharma: http://intecpharma.com/pipleline/ap-cdld/

7. Neuroderm. (n.d.). Retrieved from Neuroderm: http://neuroderm.com/nd0612-for-moderate-pd/

8. Poewe, W. a. (2015). Novel Formulations and Modes of Delivery of Levodopa. Movement Disorders, 114-120.

9. Acorda Therapeutics. (n.d.). Retrieved from Acorda Therapeutics: http://www.acorda.com/products/research-development/cvt-301